Benztropine compounds and uses thereof

ABSTRACT

Disclosed are benztropine analogs having the formula (I) 
     
       
         
         
             
             
         
       
     
     in which Ar is a C 6 -C 20  monocyclic aryl group or a C 10 -C 20  bicyclic aryl group or a heteroaryl, heterocyclic, or arylheterocyclic group having 2 to 12 carbon atoms and one or more heteroatoms selected from the group consisting of N, O, S, P, and any combination thereof; m=1 to 5; n=1 to 3; and R 1  to R 4  are as described in the specification; or a pharmaceutically acceptable salt or solvate thereof; pharmaceutical compositions and use thereof, e.g., in treating mental disorders.

BACKGROUND OF THE INVENTION

The present invention relates generally to a family of benztropinecompounds or tropane analogs, pharmaceutical compositions comprisingthem, and their use to treat various diseases or conditions includingmental disorders.

The significant public health and social problems resulting from cocaineabuse have stimulated research efforts directed toward elucidating thecentral mechanisms by which cocaine exerts its behavioral effects. Thedata from these studies suggest that the primary mechanism of thebehavioral effects of cocaine appears to be related to the inhibition ofdopamine uptake (see, Ritz, M. C., et al., Science, 237, 1219-1223(1987); and Kuhar, M. J., et al., Trends Neurosci., 14, 299-301 (1991))which results in an elevated concentration of dopamine in the synapse.As a consequence, considerable emphasis has been directed toward thedopamine transporter as a target for research and potential therapeuticsfor the treatment of cocaine abuse.

There have been several approaches to finding tropane analogs aspotential medications for psychostimulant abuse and other mentaldisorders; see, for example, Singh, S., Chem. Rev., 100, 925-1024(2000); Newman A. H. and Kulkarni S. S., Med. Res. Rev., 22, 429-464(2002); Newman, A. H., Med. Chem. Res., 8, 1-11 (1998); Carroll, F. I.,J. Med. Chem., 46, 1775-1794 (2003), Agoston et al., J. Med. Chem., 40,4329-39 (1997); Desai et al., J. Neurosci., 25, 1889-93 (Feb. 23, 2005);Kulkarni et al., J. Med. Chem., 47, 3388-98 (2004); Xu et al., J. Med.Chem., 45, 1203-10 (2002); Zou et al., Bioorg. Med. Chem. Lett., 12,1249-52 (2002); Zou et al., J. Med. Chem., 46, 2908-16 (2003); and U.S.Pat. 5,792,775. Although some of the reported analogs have demonstratedsome cocaine-like discriminative stimulus effects, there remains a needfor tropane or benztropine analogs which have affinity for the dopaminetransporter but without a significant behavioral profile of cocaine. Thepresent invention provides such analogs. This and other objects andadvantages of the invention, as well as additional inventive featureswill be apparent from the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION

The foregoing need has been fulfilled by the present invention whichprovides a family of tropane analogs. Particularly, the presentinvention provides a family of benztropine analogs having the Formula I:

in which R¹ is selected from the group consisting of hydrogen, C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₆-C₂₀ aryl C₁-C₁₂ alkyl, C₅-C₂₀heteroaryl C₁-C₁₂ alkyl, C₁-C₁₂ aminoalkyl, C₁-C₁₂ alkoxy C₁-C₁₂ alkyl,C_(s)-C₂₀ heterocycloalkyl C₁-C₁₂ alkyl, C₁-C₁₂ alkylsulfonyl, C₂-C₁₂alkylcarbonyl, (N(C₆-C₂₀ aryl)amido)C₁-C₁₂ alkyl, (N(C₁-C₁₂alkyl)amido)C₁-C₁₂ alkyl, (N(C₆-C₂₀ aryl)amido)C₂-C₁₂ alkylcarbonyl,(N(C₁-C₁₂ alkyl)amido)C₂-C₁₂ alkylcarbonyl, C₁-C₁₂ alkylamido C₆-C₂₀aryl, and a polymer; m=1 to 5; n=1 to 3; R² and R³ are eachindependently selected from the group consisting of hydrogen, halo,C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, nitro, cyanato, isocyanato, thiocyanato,amino, halo C₁-C₁₂ alkyl, hydroxyl, trihalo C₁-C₁₂ alkyl, and anycombination thereof; R⁴ is selected from the group consisting ofhydroxyl, carboxyl, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, C₂-C₁₂ carboxyalkyl,C₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkyloxycarbonyl, C₆-C₂₀ aryl oxycarbonyl,C₆-C₂₀ aryl C₂-C₁₂ alkyloxycarbonyl, C₂-C₁₂ alkyloxycarbonyl C₁-C₁₂alkyl, C₆-C₂₀ aryl, C₆-C₂₀ aryl C₂-C₁₂ alkylcarbonyloxy C₁-C₁₂ alkyl,C₁-C₁₂ alkylsulfonyl, C₁-C₁₂ hydroxyalkyl, formyl, C₂-C₁₂ formylalkyl,C₂-C₁₂ alkenyl, C₂-C₁₂ alkyloxycarbonyl C₂-C₁₂ alkenyl, and C₂-C₁₂alkynyl; Ar is a C₆-C₂₀ monocyclic aryl group or a C₁₀-C₂₀ bicyclic arylgroup or a heteroaryl, heterocyclic, or aryl heterocyclic group having 2to 12 carbon atoms and one or more heteroatoms selected from the groupconsisting of N, O, S, P, and any combination thereof; and wherein anyof R¹, R², R³, and R⁴ other than hydrogen, halo, hydroxyl, nitro,cyanato, isocyanato, and thiocyanato can be further substituted with oneor more substituents selected from the group consisting of halo,hydroxyl, cyanato, isocyanato, thiocyanato, amino, C₁-C₁₂ alkyl, amido,nitro, methoxy, CF₃, azido, C₂-C₁₂ alkylcarbonyl, amino, C₁-C₁₂alkylamino, C₂-C₁₂ alkylcarbonyl, and any combination thereof; or apharmaceutically acceptable salt or solvate thereof.

The benztropine analogs of the present invention have an affinity forthe dopamine transporter and inhibit dopamine uptake, but they do notproduce a significant stimulation of locomotor activity or cocaine-likesubjective effects in a drug discrimination model. The benztropineanalogs have one or more advantageous properties, e.g., improved watersolubility, increased stability, and/or selectivity.

The benztropine analogs of the present invention find use astherapeutics, e.g., cocaine antagonists or cocaine substitutes, for thetreatment of cocaine abuse. The present invention also provides methodsof treating a patient for a mental disorder.

The present invention further provides a method of administering abenztropine compound of Formula III

in which R¹-R³ are as described herein, to a mammal to increaseattention to relevant signals (stimuli) in the environment relative toan untreated control, reduce the effect of nicotine by at least 50%,and/or reduce food intake.

The benztropine analogs of the present invention find use as imagingprobes for dopamine transporter/cocaine binding sites and as imagingprobes for neurodegenerative disorders (e.g., Parkinson's disease). Thepresent invention also provides a method of selectively imaging cocainebinding sites of the central nervous system of a human patient, themethod comprising administering to the central nervous system of thepatient a compound described above and detecting the binding of thatcompound to the central nervous system tissue.

The present invention also provides a method of detecting or monitoringParkinsonism in a patient, the method comprising administering to thepatient a detectably labeled compound described above and detecting thebinding of that compound to the central nervous system tissue. Usingthis method, one can diagnose and/or monitor Parkinson's disease, aneurological disorder characterized by the progressive degeneration ofdopamine nerve terminals.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 (A-F) illustrates the effects of 2-substituted BZT analogues inrats measured as (i) a percentage of responses on thecocaine-appropriate lever (A, B, and C) or (ii) rates at which responseswere emitted as a percentage of responses after saline administration(D, E, and F) versus drug dose (μmol/kg) (log scale).

FIG. 2 graphically illustrates locomotor activity counts after drugadministration versus time since injection and placement of subject inthe experimental chamber. Each point represents the average effectdetermined in six to eight mice, for successive 10-min time periods upto 480 min (8 h) after injection. FIG. 2A represents injection of 1a.FIG. 2B represents injection of 1b. FIG. 2C represents injection of MFZ2-74 (R¹=Me; R^(2,3)═F; R⁴═CO₂-^(i)Pr). FIG. 2D represents injection of15. FIG. 2E represents injection of 14.

FIG. 3 graphically illustrates specific [¹²⁵I]RTI-121 binding as apercentage of that obtained after vehicle injection versus time. Foreach point the number of replicates was from 5 to 10. FIG. 3A representsinjection of 1a. FIG. 3B represents injection of 1b. FIG. 3C representsinjection of MFZ 2-74 (R¹=Me; R^(2,3)═F; R⁴═CO₂-^(i)Pr). FIG. 3Drepresents injection of 15. FIG. 3E represents injection of 14.

FIG. 4A illustrates a representative control performance measuringcumulative responses (both correct detections of a stimulus and errors)over time. FIG. 4B illustrates the same performance after administrationof a compound of formula III.

FIG. 5 illustrates reduction of food intake (g), after administration ofcompounds of formula III (mg/kg).

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides compounds having thegeneral Formula I:

or a pharmaceutically acceptable salt or solvate thereof.

In Formula I, R¹ is selected from the group consisting of hydrogen,C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₆-C₂₀ aryl C₁-C₁₂ alkyl,C₅-C₂₀ heteroaryl C₁-C₁₂ alkyl, C₁-C₁₂ aminoalkyl, C₁-C₁₂ alkoxy C₁-C₁₂alkyl, C₅-C₂₀ heterocycloalkyl C₁-C₁₂ alkyl, C₁-C₁₂ alkylsulfonyl,C₂-C₁₂ alkylcarbonyl, (N(C₆-C₂₀ aryl)amido)C₁-C₁₂ alkyl, (N(C₁-C₁₂alkyl)amido)C₁-C₁₂ alkyl, (N(C₆-C₂₀ aryl)amido)C₂-C₁₂ alkylcarbonyl,(N(C₁-C₁₂ alkyl)amido)C₂-C₁₂ alkylcarbonyl, C₁-C₁₂ alkylamido C₆-C₂₀aryl, and a polymer. The polymer can be any pharmaceutically acceptablepolymer. Preferably, the polymer is one that will not decrease thesolubility of the compound, such as a hydrophilic polymer, for example,polyalkylene glycols such as polyethylene glycol, dextrans,polyglutamates, polylactides, and the like. Typically, R¹ is selectedfrom the group consisting of hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₆-C₂₀ aryl-C₁-C₁₂ alkyl, C₁-C₁₂ aminoalkyl, C₅-C₂₀heterocycloalkyl-C₁-C₁₂ alkyl, and (N(C₆-C₂₀-aryl)amido)C₁-C₁₂ alkyl.Preferably, R¹ is selected from the group consisting of hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₆-C₁₀ aryl-C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₅-C₁₀heterocycloalkyl-C₁-C₆ alkyl, and (N(C₆-C₁₀-aryl)amido)C₁-C₆ alkyl. Morepreferably, R¹ is selected from the group consisting of methyl, ethyl,propyl, butyl, allyl, phenylbutyl, 2-aminoethyl,[2-(1H-indol-3-yl)-ethyl]-, and 3-[(N-phenyl)amidopropyl].

The group Ar in Formula I is a C₆-C₂₀ monocyclic aryl group, a C₁₀-C₂₀bicyclic aryl group, or a heteroaryl group, heterocyclic, orarylheterocyclic group having 2 to 12 carbon atoms and one or moreheteroatoms selected from the group consisting of N, O, S, P, and anycombination thereof. Typically Ar is selected from the group consistingof phenyl, naphthyl, biphenyl, pyridyl, bipyridyl, pyrimidyl, pyrrolyl,furanyl, thiophenyl, triazolyl, triazolopyrimidyl, thiadiazolyl,phosphole, diazaphosphole, quinoxalyl, benzofuranyl, benzopyrrolyl,morpholinyl, benzopyranyl, oxolyl, thiazolyl, purinyl, imidazolyl,indolyl, phosphindolyl (C₈H₆P−), pyrazolyl, and isoindolyl. Preferably,Ar is phenyl or naphthyl. More preferably, Ar is phenyl.

R² and R³ are each independently selected from the group consisting ofhydrogen, halo, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, nitro, cyanato, isocyanato,thiocyanato, amino, halo C₁-C₁₂ alkyl, hydroxyl, trihalo C₁-C₁₂ alkyl,and any combination thereof. Typically, R² and R³ are selected from thegroup consisting of hydrogen, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, nitro,cyanato, isocyanato, thiocyanato, amino, halo C₁-C₆ alkyl, hydroxyl,trihalo C₁-C₆ alkyl, and any combination thereof. Preferably R² isfluoro, chloro, or hydrogen and/or R³ is fluoro or chloro. Morepreferably, R² and R³ are fluoro.

The number of groups R² (m) and R³ (n) present in Formula I is m=1 to 5and n=1 to 3, respectively. In some embodiments, the phenyl and Ar ringseach can have only one substituent such that m=n=1. In otherembodiments, the phenyl ring can have one or two substituents (n is 1 or2) while the Ar ring(s) can have 1 to 5 substituents (m=1 to 5). R² andR³ can occupy any suitable position. Preferably R² and R³ do not occupya position that is ortho to the methylene linkage, e.g., they occupymeta- and/or para-positions.

R⁴ is selected from the group consisting of hydroxyl, carboxyl, C₁-C₁₂alkyl, C₁-C₁₂ alkoxy, C₂-C₁₂ carboxyalkyl, C₂-C₁₂ alkylcarbonyl, C₂-C₁₂alkyloxycarbonyl, C₆-C₂₀ aryl oxycarbonyl, C₆-C₂₀ aryl C₂-C₁₂alkyloxycarbonyl, C₂-C₁₂ alkyloxycarbonyl C₁-C₁₂ alkyl, C₆-C₂₀ aryl,C₆-C₂₀ aryl C₂-C₁₂ alkylcarbonyloxy C₁-C₁₂ alkyl, C₁-C₁₂ alkylsulfonyl,C₁-C₁₂ hydroxyalkyl, formyl, C₂-C₁₂ formylalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkyloxycarbonyl C₂-C₁₂ alkenyl, and C₂-C₁₂ alkynyl. In someembodiments, R⁴ desirably is selected from the group consisting ofhydroxyl, carboxyl, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, C₂-C₁₂ carboxyalkyl,C₂-C₁₂ alkyloxycarbonyl C₁-C₁₂ alkyl, C₆-C₂₀ aryl, C₆-C₂₀ aryl C₂-C₁₂alkylcarbonyloxy C₁-C₁₂ alkyl, C₁-C₁₂ alkylsulfonyl, C₁-C₁₂hydroxyalkyl, formyl, C₂-C₁₂ formylalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkyloxycarbonyl C₂-C₁₂ alkenyl, and C₂-C₁₂ alkynyl. In otherembodiments, R⁴ desirably is selected from the group consisting ofC₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkyloxycarbonyl, C₅-C₂₀ aryloxycarbonyl,and C₆-C₂₀ aryl C₂-C₁₂ alkyloxycarbonyl. Typically R⁴ is selected fromthe group consisting of hydroxyl, carboxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₂-C₆ carboxyalkyl, C₂-C₆ alkylcarbonyl, C₂-C₆ alkyloxycarbonyl, C₆-C₁₀aryl oxycarbonyl, C₆-C₁₀ aryl C₂-C₆ alkyloxycarbonyl, C₂-C₆alkyloxycarbonyl C₁-C₆ alkyl, C₆-C₁₀ aryl, C₆-C₁₀ aryl C₂-C₆alkylcarbonyloxy C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, C₁-C₆ hydroxyalkyl,formyl, C₂-C₆ formylalkyl, C₂-C₆ alkenyl, C₂-C₆ alkyloxycarbonyl C₂-C₆alkenyl, and C₂-C₆ alkynyl. Preferably R⁴ is selected from the groupconsisting of methyloxycarbonyl, ethyloxycarbonyl, hydroxymethyl,formyl, methyloxycarbonylethenyl, methyloxycarbonylethyl, ethenyl,4-nitrophenylpropylcarbonyloxyethyl, and4-aminophenylpropylcarbonyloxyethyl. More preferably R⁴ is selected fromthe group consisting of ethenyl, hydroxymethyl,methyloxycarbonylethenyl, and methyloxycarbonylethyl.

Any of the groups R¹, R², R³, and R⁴, other than hydrogen, halo,hydroxyl, nitro, cyanato, isocyanato, and thiocyanato can be furthersubstituted with one or more substituents selected from the groupconsisting of halo, hydroxyl, cyanato, isocyanato, thiocyanato, amino,C₁-C₁₂ alkyl, amido, nitro, methoxy, CF₃, azido, C₂-C₁₂ alkylcarbonyl,amino, C₁-C₁₂ alkylamino, C₂-C₁₂ alkylcarbonyl, and any combinationthereof.

The term “independently selected” is used herein to indicate that thetwo R groups, i.e., R² and R³, can be identical or different (e.g., R²and R³ may both be methoxy), two or more R² groups can be identical ordifferent, or two or more R³ groups can be identical or different.

The phrase “pharmaceutically acceptable salt” is intended to includenontoxic salts synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remington's Pharmaceutical Sciences, 18th ed., Mack PublishingCompany, Easton, Pa., 1990, p. 1445, and Journal of PharmaceuticalScience, 66, 2-19 (1977).

Suitable bases include inorganic bases such as alkali and alkaline earthmetal bases, e.g., those containing metallic cations such as sodium,potassium, magnesium, calcium and the like. Suitable acids includeinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, phosphoric acid, and the like, and organic acidssuch as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid,oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid,citric acid, benzoic acid, acetic acid, fatty acids, long chain fattyacids, and the like. Examples of such pharmaceutically acceptable saltsare the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, bromide, hydrobromide, iodide, acetate, propionate,caprate, caprylate, acrylate, ascorbate, formate, hydrochloride,dihydrochloride, isobutyrate, caproate, heptanoate, propiolate,glucuronate, glutamate, propionate, phenylpropionate, salicylate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, behenate, oleate, mandelate, nicotinate,isonicotinate, cinnamate, hippurate, nitrate, stearate, phthalate,terephthalate, butyne-1,4-dioate, butyne-1,4-dicarboxylate,hexyne-1,4-dicarboxylate, hexyne-1,6-dioate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxybenzoate, naphthalene-2-benzoate, p-toluenesulfonate,p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate,phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate,citrate, lactate, hydroxybutyrate, glycolate, tartrate, hemi-tartrate,benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, 1-naphthalenesulfonate, 2-napththalenesulfonate,1,5-naphthalenedisulfonate, and the like. Preferred pharmaceuticallyacceptable acid addition salts are those formed with mineral acids suchas hydrochloric acid and hydrobromic acid, and those formed with organicacids such as maleic acid, oxalic acid and methanesulfonic acid.Preferred pharmaceutically acceptable salts are hydrochloride,hydrobromide, oxalate, maleate, methanesulfonate, and hemi-tartrate. Aparticularly preferred pharmaceutically acceptable salt ishydrochloride. The compounds of the present invention are useful in theform of the free base or acid or in the form of a pharmaceuticallyacceptable salt thereof.

It should be recognized that the particular counter ion forming a partof any salt of this invention is usually not of a critical nature, solong as the salt as a whole is pharmacologically acceptable and as longas the counter ion does not contribute undesired qualities to the saltas a whole.

It is further understood that the above compounds and salts may formsolvates, or exist in a substantially uncomplexed form, such as theanhydrous form. As used herein, the term “solvate” refers to a molecularcomplex wherein the solvent molecule, such as the crystallizing solvent,is incorporated into the crystal lattice. When the solvent incorporatedin the solvate is water, the molecular complex is called a hydrate.Pharmaceutically acceptable solvates include hydrates, alcoholates suchas methanolates and ethanolates, acetonitrilates and the like. Thesecompounds can also exist in polymorphic forms.

Within the scope of Formula I, certain embodiments are preferred, forexample, when the substituent R⁴ is in the β-position as shown inFormula II.

For example, preferred compounds include those of Formula I or II inwhich R¹ is selected from the group consisting of hydrogen, C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₆-C₂₀ aryl-C₁-C₁₂ alkyl, C₁-C₁₂ aminoalkyl,C₅-C₂₀ heterocycloalkyl-C₁-C₁₂ alkyl, and (N(C₆-C₂₀-aryl)amido)C₁-C₁₂alkyl; m=n=1; Ar is phenyl; R² and R³ are halo; and R⁴ ismethyloxycarbonyl, ethyloxycarbonyl, hydroxymethyl, formyl,methyloxycarbonylethenyl, methyloxycarbonylethyl, ethenyl,4-nitrophenylpropylcarbonyloxyethyl, or4-aminophenylpropylcarbonyloxyethyl. In some embodiments, R¹ is selectedfrom the group consisting of hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₆-C₁₀ aryl-C₁-C₆ alkyl, C₁-C₆ aminoalkyl, C₅-C₁₀ heterocycloalkyl-C₁-C₆alkyl, and (N(C₆-C₁₀-aryl)amido)C₁-C₆ alkyl; m=n=1; Ar is phenyl; R² andR³ are halo; and R⁴ is methyloxycarbonyl, ethyloxycarbonyl,hydroxymethyl, formyl, methyloxycarbonylethenyl, methyloxycarbonylethyl,ethenyl, 4-nitrophenylpropylcarbonyloxyethyl, or4-aminophenylpropylcarbonyloxyethyl. Also preferred are compounds inwhich R¹ is selected from the group consisting of methyl, n-butyl,allyl, phenylbutyl, 2-aminoethyl, [2-(1H-indol-3-yl)-ethyl]-, and3-[(N-phenyl)amidopropyl]; m=n=1; Ar is phenyl; R² and R³ are halo; andR⁴ is methyloxycarbonyl, ethyloxycarbonyl, hydroxymethyl, formyl,methyloxycarbonylethenyl, methyloxycarbonylethyl, ethenyl,4-nitrophenylpropylcarbonyloxyethyl, or4-aminophenylpropylcarbonyloxyethyl.

In some embodiments of Formula I or II, R¹ is selected from the groupconsisting of hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₆-C₂₀ aryl-C₁-C₁₂alkyl, C₁-C₁₂ aminoalkyl, C₅-C₂₀ heterocycloalkyl-C_(I)-C₁₂ alkyl, and(N(C₆-C₂₀-aryl)amido)C₁-C₁₂ alkyl; m=n=1; Ar is phenyl; R² and R³ arechloro or fluoro; and R⁴ is methyloxycarbonyl, ethyloxycarbonyl,hydroxymethyl, formyl, methyloxycarbonylethenyl, methyloxycarbonylethyl,ethenyl, 4-nitrophenylpropylcarbonyloxyethyl, or4-aminophenylpropylcarbonyloxyethyl; specifically R¹ is selected fromthe group consisting of hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₆-C₂₀aryl-C₁-C₁₂ alkyl, C₁-C₁₂ aminoalkyl, C₅-C₂₀ heterocycloalkyl-C₁-C₁₂alkyl, and (N(C₆-C₂₀-aryl)amido)C₁-C₁₂ alkyl; m=n=1; Ar is phenyl; R²and R³ are 4-chloro or 4-fluoro; and R⁴ is methyloxycarbonyl,ethyloxycarbonyl, hydroxymethyl, formyl, methyloxycarbonylethenyl,methyloxycarbonylethyl, ethenyl, 4-nitrophenylpropylcarbonyloxyethyl, or4-aminophenylpropylcarbonyloxyethyl; and particularly R¹ is selectedfrom the group consisting of hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl,C₆-C₂₀ aryl-C₁-C₁₂ alkyl, C₁-C₁₂ aminoalkyl, C_(s)-C₂₀heterocycloalkyl-C₁-C₁₂ alkyl, and (N(C₆-C₂₀-aryl)amido)C₁-C₁₂ alkyl; m=n=1; Ar is phenyl; R² and R³ are 4-chloro or 4-fluoro; and R⁴ ismethyloxycarbonyl or ethyloxycarbonyl. More particularly preferredcompounds are selected from the group consisting of:

In other embodiments of Formula I or II, m=n=1; Ar is phenyl; R¹ isselected from the group consisting of hydrogen, methyl, n-butyl, allyl,phenylbutyl, 2-aminoethyl, [2-(1H-indol-3-yl)-ethyl]-, and3-[(N-phenyl)amidopropyl]; R² and R³ are 4-fluoro or 4-chloro; and R⁴ ishydroxymethyl, formyl, methyloxycarbonylethenyl, methyloxycarbonylethyl,ethenyl, 4-nitrophenylpropylcarbonyloxyethyl, or4-aminophenylpropylcarbonyloxyethyl; specifically m=n=1; Ar is phenyl;R¹ is methyl; R² and R³ are 4-fluoro or 4-chloro; and R⁴ ishydroxymethyl, formyl, methyloxycarbonylethenyl, methyloxycarbonylethyl,ethenyl, 4-nitrophenylpropylcarbonyloxyethyl, or4-aminophenylpropylcarbonyloxyethyl. More particularly preferredcompounds are selected from the group consisting of:

In yet other embodiments of Formula I or II, m=n=1; Ar is phenyl; R¹ isselected from the group consisting of hydrogen, methyl, ethyl, 2-propyl,(CH₂)_(p)CH₃, CH₂CF₃, CH₂(CH₂)_(p)OH, CH₂(CH₂)_(p)O(CH₂)_(q)CH₃,CH₂CH═CHX, 2-(1-piperidinyl)ethyl, 2-(4-morpholinyl)ethyl, and(CH₂)_(p)C₆H₄X, wherein X is selected from the group consisting of H,halo, hydroxyl, methoxy, CF₃, nitro, amino, cyanato, NHCOCH₃, N(CH₃)₂,(CH₂)_(p)CH₃, azido, C(O)CH₃, and C(CH₃)₃; p=0-6; q=0-4; R⁴ is selectedfrom the group consisting of C₂-C₁₂ alkylcarbonyl, C₂-C₁₂alkyloxycarbonyl, C₅-C₂₀ aryloxycarbonyl, and C₆-C₂₀ aryl C₂-C₁₂alkyloxycarbonyl; and at least one of R² and R³ is selected from thegroup consisting of C₁-C₁₂ alkyl, C₂-C₁₂ alkoxy, nitro, cyanato,isocyanato, thiocyanato, amino, halo C₁-C₁₂ alkyl, and trihalo C₁-C₁₂alkyl.

It should be noted, however, that for compounds of Formula II, if Ar isphenyl, m=n=1, R¹ is CH₃, and R⁴ is COOCH₃, both R² and R³ are notsimultaneously hydrogen, 4-halo or 4-methyl. In addition, if Ar isphenyl, m=n=1, R¹ is CH₃, and R² and R³ are 4-fluoro, R⁴ is not COOC₂H₅,CO₂CH(CH₃)₂, CO₂CH₂Ph, CO₂CH₂CH₂Ph, CO₂CH₂CH₂Ph-4′-NO₂,CO₂CH₂CH₂Ph-4′-NH₂, CO₂CH₂CH₂Ph-3′-I, 4′-NH₂, CO₂CH₂CH₂Ph-3′-I, 4′-N₃,or CO₂CH₂CH₂Ph-4′-NCS. Also, if Ar is phenyl, m=n=1, R¹ is CH₃, R⁴ isCOOCH₃, and R² is hydrogen, R³ is not 4-halo or 4-methyl, oralternatively if Ar is phenyl, m=n=1, R¹ is CH₃, R⁴ is COOCH₃, and R² is4-bromo, R³ is not 4-iodo. Moreover, if Ar is phenyl, m=1, n=2, R¹ isCH₃, R⁴ is COOCH₃, and R² is hydrogen, R³ is not hydroxyl, 2-propoxyl,alkoxyl, or methylcarbonyloxy.

The compounds of Formula I or II can be prepared by any suitable method,for example, by using the synthetic schemes set forth in Schemes 1-3. Asshown in Scheme 1, a (S)-2β-carboalkoxybenztropine compound is reducedto form the corresponding (S)-2β-alcohol. A subsequent Swern oxidationof the (S)-2β-alcohol compound provides the corresponding(S)-2β-aldehyde analog. A Wittig reaction of the (S)-2β-aldehydecompound with methyltriphenylphosphonium bromide gives the (S)-2β-alkeneanalog. Alternatively, Musamune-Rousch olefination of the(S)-2β-aldehyde with trimethylphosphonoacetate produces the(S)-2β-unsaturated ester. Catalytic hydrogenation of the(S)-2β-unsaturated ester gives the (S)-2β-saturated ester compound.

As shown in Scheme 2, the (S)-2β-alcohol compound can also be reactedwith 4-(p-nitrophenyl)butyric acid chloride to produce the(S)-2β-methyl-4-(p-nitrophenyl)butyric acid ester compound. Subsequentreduction of the nitro group with Raney Ni produces the aniline analog.

It will be readily apparent to those of skill in the art that theN-methyl group on the tropane can be substituted with other functionalgroups using standard chemical reactions known to them. For example, theN-methyl group can be replaced with other functional groups including,but not limited to, hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, C₆-C₂₀ aryl C₁-C₁₂ alkyl, C₅-C₂₀ heteroaryl C₁-C₁₂ alkyl,C₁-C₁₂ alkylamino, C₅-C₂₀ heterocycloalkyl C₁-C₁₂ alkyl, C₁-C₁₂alkylsulfonyl, C₂-C₁₂ alkylcarbonyl, (N(C₆-C₂₀aryl)amido)C₁-C₁₂ alkyl,(N(C₁-C₁₂ alkyl)amido)C₁-C₁₂ alkyl, and a polymer. Alternatively,alkylation can occur upon reaction with the appropriate acid in thepresence of DCC (dicyclohexylcarbodiimide) and HOBt(1-hydroxybenzotriazole hydrate). For example, the functional groupR⁴=[2-(1H-indol-3-yl)-ethyl]- can be obtained by reaction with2-indoleacetic acid. In particular as shown in Scheme 3, the benztropinenitrogen of the (S)-2β-carboalkoxybenztropine compound can be modifiedby demethylation reaction following the Oloffson procedure. The N-allyland N-butyl compounds are generated by subsequent reaction with allylbromide and butyl bromide, respectively.

In order to understand the neurochemical and behavioral properties ofthe compounds of the present invention, exemplary benztropine analogswere evaluated for displacement of [³H]WIN 35,428(2β-carbomethoxy-3β-(4-fluorophenyl)tropane) binding to the DAT in ratcaudate-putamen. These benztropine analogs were also evaluated fordisplacement of radiolabeled ligand binding at the serotonin (SERT) andnorepinephrine (NET) transporters as well as the muscarinic m₁ receptor(M1), Tables 1 and 2, infra. The NET over DAT selectivity refers to theratio of respective K_(i) values. When the K_(i) ratio is greater than1, the compound is DAT selective. The DAT selectivities of the analogsover these binding sites are depicted in Table 3.

TABLE 1 Inhibition constants (K_(i)) at the monoamine transporters andthe muscarinic M1 receptor in rat brain membranes^(a)

DAT SERT NET M₁ [³H]WIN 35,428 [³H]citalopram [³H]nisoxetine[³H]pirenzepine Compound R¹ R⁴ K_(i) ± SEM (nM) K_(i) ± SEM (nM) K_(i) ±SEM (nM) K_(i) ± SEM (nM)  1a CH₃ COOCH₃ 2.94 ± 0.36  689 ± 58.4   269 ±38.9^(b)  133 ± 4.16  2 CH₃ CH₂OH 3.52 ± 0.42 910 ± 65   983 ± 97.0  109± 15.1  4 CH₃ CH═CH₂ 1.81 ± 0.21 1790 ± 114   473 ± 64.2  163 ± 23.1  5CH₃ CH═CHCO₂CH₃ 4.69 ± 0.60 572 ± 51   269 ± 34.8 1380 ± 81.0   6 CH₃CH₂CH₂CO₂CH₃ 3.74 ± 0.07 1070 ± 118   454 ± 43.2 3110 ± 435   7 CH₃CH₂OCO(CH₂)₃C₆H₄NO₂-p 39.9 ± 4.31 3780 ± 390  2130 ± 157  708 ± 102  8CH₃ CH₂OCO(CH₂)₃C₆H₄NH₂-p 27.6 ± 0.85 1390 ± 145   440 ± 17.7  342 ±33.7  1b CH₃ COOCH₂CH₃ 6.87 ± 0.33 1850 ± 270  629 ± 31^(b) 1890 ± 132  9 H COOCH₂CH₃ 8.87 ± 1.02 2150 ± 222   563 ± 73.9 17100 ± 2480  10 butyl COOCH₂CH₃ 8.18 ± 0.17 2500 ± 327   580 ± 15.9 3200 ± 298  11 allyl COOCH₂CH₃ 11.0 ± 0.94 2280 ± 125  935 ± 113 11400 ± 1650  12^(c)butyl H 9.70 ± 0.91 1350 ± 151  1490 ± 190   399 ± 26.8 13^(c) allyl H8.79 ± 0.52 2850 ± 62.5 1570 ± 242   177 ± 21.1 ^(a)Each K_(i) valuerepresents data from at least three independent experiments, eachperformed in triplicate. K_(i) values were analyzed by PRISM. Thebinding assay methods were conducted as reported previously (seeKulkarni S., J. Med. Chem., 47, 3388-98 (2004)) except that the DATassay was run in sucrose buffer. ^(b)Incubation time was 1 h; for allothers incubation time was 3 h. ^(c)Comparative data taken from Agostonet al. (J. Med. Chem., 40, 4329-39 (1997))

TABLE 2 Binding data for (S) and (±)-2-substituted3α-[bis(4-chlorophenyl)methoxy]tropanes.

DAT binding DA uptake SERT NET M₁ Compound R¹ R⁴ K_(i) ^(a,b)(nM) IC₅₀^(a,b)(nM) K_(i) ^(a,b)(nM) K_(i) ^(a,b)(nM) K_(i) ^(a,b)(nM) S-14 CH₃COOCH₃ 12.6 ± 0.40 2.46 ± 0.2  528 ± 39  2150 ± 325 382 ± 37 (±)-14 CH₃COOCH₃ 23.4 ± 1.5  NT NT NT NT S-15 CH₃ COOCH₂CH₃ 14.6 ± 0.39 1.52 ±0.2  1560 ± 91  3350 ± 154 3060 ± 150 (±)-15 CH₃ COOCH₂CH₃ 22.0 ± 0.84NT NT NT NT 4,4-diCl BZT^(d) CH₃ H  17.5 ± 0.88^(e) 23.4 ± 3.0^(c)  1640± 236^(c)   2980 ± 182^(c)  40.6 ± 8.0^(c) ^(a)Each K_(i) valuerepresents data from at least three independent experiments, eachperformed in triplicate. K_(i) values were analyzed by PRISM.^(b)Binding methods were conducted as previously reported ((Katz et al.,Psychopharmacology, 154, 362-374 (2001) and Kulkarni et al., J. Med.Chem., 47, 3388-3398 (2004)) except that the DAT assay was run insucrose buffer. ^(c)Data from Katz et al., Psychopharmacology, 154,362-374 (2001) and included for reference.^(d)3α-(bis-Cl-phenylmethoxy)tropane. ^(e)The K_(i) values for thesecompounds at DAT were assessed using different methods (Katz et al.,Psychopharmacology, 154, 362-374 (2001) and Kulkarni et al., J. Med.Chem., 47, 3388-3398 (2004)) than those used for the other compounds. Inour experience the values obtained using those methods give K_(i) valuesthat are approximately three-fold higher than those obtained with themethods used for the other compounds. NT = not tested.

TABLE 3 Binding selectivities for the benztropine analogs CompoundDAT/SERT DAT/NET DAT/M₁  1a 234 91 45  2 258 279 31  4 989 261 90  5 11554 278  6 286 121 831  7 94 53 18  8 50 16 12  1b 269 91 275  9 242 631928 10 305 71 391 11 207 85 1036 12 139 153 41 13 324 178 20

All of the compounds displaced [³H]WIN 35,428 binding at the dopaminetransporter with high affinity (K_(i)=1.81 to 39.9 nM). The most potentcompound in this exemplary series is compound 4, K_(i)=1.81 nM. None ofthese compounds demonstrate high affinity to the NET, SERT or muscarinicMl receptors. All compounds showed high selectivity in binding to theDAT over SERT, NET and muscarinic M1 receptor except for compounds 7 and8, which showed reduced DAT/M1 selectivity. Compound 9 is the mostDAT/M1 selective benztropine compound reported to date.

A comparison between compound 1a and compounds 5 and 6 reveals thatincreasing the chain length at the 2-position does not significantlyaffect binding affinity to the DAT (2.94 nM v. 4.96 nM and 3.74 nM,respectively). N-Demethylation to the N-nor analog and substitution withN-n-butyl or N-allyl slightly decreases binding affinitiy to the DATcompared to the parent compounds 1a and 1b. Conversely, addition of the2β-COOEt to compounds 12 or 13 had no effect on DAT binding butsignificantly improved DAT/M1 selectivity.

The benztropine analogs of the present invention find use astherapeutics for the treatment of a mental disorders, e.g., thoseselected from the group consisting of conduct disorders, alcoholaddiction, tobacco addiction, nicotine addiction, drug addiction, sleepdisorders, obesity by reducing food intake, inhalation disorders,Parkinsonism including Parkinson's disease, female and male orgasmicdisorders, female and male sexual arousal disorders, hypoactive sexualdesire disorder, and anxiety, stress and/or depression disorders.Preferably, the benztropine analogs are used to treat cocaine abuse,narcolepsy or cataplexy, obesity by reducing food intake, tobaccoaddiction, nicotine addiction, or Attention Deficit HyperactivityDisorder (ADHD). More preferably, the benztropine analogs are used totreat cocaine abuse.

In an embodiment of the inventive method, in particular, treatment ofADHD, obesity by reducing food intake, tobacco addiction, and/ornicotine addiction, the compound of Formula I or II has m=n=1; Ar isphenyl; R¹ is selected from the group consisting of hydrogen, C₁-C₁₂alkyl (e.g., methyl, ethyl, 2-propyl), (CH₂)_(p)CH₃, CH₂CF₃,CH₂(CH₂)_(p)OH, CH₂(CH₂)_(p)O(CH₂)_(q)CH₃, CH₂CH═CHX,2-(1-piperidinyl)ethyl, 2-(4-morpholinyl)ethyl, and (CH₂)_(p)C₆H₄X,wherein X is selected from the group consisting of H, halo, hydroxyl,methoxy, CF₃, nitro, amino, cyanato, NHCOCH₃, N(CH₃)₂, (CH₂)_(p)CH₃,azido, C(O)CH₃, and C(CH₃)₃; p=0-6; q=0-4; R⁴ is selected from the groupconsisting of C₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkyloxycarbonyl, C₅-C₂₀aryloxycarbonyl, and C₆-C₂₀ aryl C₂-C₁₂ alkyloxycarbonyl; and at leastone of R² and R³ is selected from the group consisting of C₁-C₁₂ alkyl,C₂-C₁₂ alkoxy, nitro, cyanato, isocyanato, thiocyanato, amino, halo,halo C₁-C₁₂ alkyl, and trihalo C₁-C₁₂ alkyl. Preferably, the compound ofFormula I or II used in the inventive method has m=n=1; Ar is phenyl; R¹is selected from the group consisting of C₁-C₁₂ alkyl (e.g., methyl); R⁴is C₂-C₁₂ alkyloxycarbonyl (e.g., methyloxycarbonyl, ethyloxycarbonyl;i-propyloxycarbonyl); and R² and R³ are the same or different and eachis selected from hydrogen and halo (e.g., F, Cl).

These compounds inhibit dopamine uptake and provide elevated levels ofextracellular dopamine that alleviate the symptoms of cocaine abstinence(see, Rothman, R. B., et al., Life Sci. Pharmacol. Lett. 1990, 46,PL-17-PL-21) in a manner similar to the way in which the nicotine patchor nicotine chewing gum protects against withdrawal symptoms aftercessation of tobacco use. Further, as a result of their lack ofcocaine-like behavioral effects, these compounds are not subject toabuse themselves. Thus, the benztropine analogs of the present inventioncan serve to keep drug abusers from seeking cocaine, but they will notbecome substitute addictive drugs.

As used herein, “cocaine abuse” has its conventional meaning, i.e.,misuse or addiction of cocaine. Conventional thought suggests thatcocaine is taken by a person due to a craving for cocaine generated byits prior use. Excessive use of cocaine produces many serious andadverse side effects. As such, it is highly desirable to reduce thenumber and/or intensity of episodes of cocaine abuse. Abstinence fromcocaine is thought to be associated with decreased dopamine levels inthe brain that result in feelings of dysphoria. If dopamine levelsremain elevated, the dysphoria will be prevented, and the individualwill not seek cocaine. As such, compounds that increase dopamine levelsfor a prolonged period of time (without causing euphoria andreinforcement that would lead to their abuse) would provide atherapeutic treatment for cocaine addiction.

The ability of these compounds to inhibit dopamine uptake and likewisecause increased and sustained dopamine levels in the brain is alsouseful for treating other addiction and mental disorders includingalcohol addiction (see Eiler et al., Synapse, 489, 45 (2003); Tupala etal., Neuroimage, 19, 145 (2003)), nicotine addiction (see Bahk et al.,Prog. Neuropsychopharmacol. Biol. Psychiatry, 26, 1095 (2002); Geraciotiet al., Am. J Psychiatry, 156, 130 (1999)); other types of drugaddiction (see Campiani et al., J. Med. Chem., 46, 3822 (2003); Chartoffet al., J. Neurochem., 38, 107 (2003); O'Shea et al., Trends Pharmacol.Sci., 24, 272 (2003)); obesity (by reducing food intake) (see U.S. Pat.6,395,748); sexual dysfunction including orgasmic disorder, female/malesexual arousal disorders, and hypoactive sexual desire disorder (seeEarler et al., Urology, 62, 727 (2003); Guiliano et al., Eur. Urol., 40,601 (2001)); sleep disorders including narcolepsy and cataplexy (seeWisor et al., J. Neurosci., 21, 1787 (2001); Honda et al., Neuroreport,10, 3713 (1999)); Parkinsonism including Parkinson's disease (see Moore,Parkinsonism Relat. Disord., 9 Suppl. 2, S65 (2003); Stocchi et al., J.Neurol., 250, 822 (2003)); conduct disorders including ADHD (see Younget al., Am. J. Med. Genet., 114, 144 (2002); Seeman et al., Behav. BrainRes., 130, 79 (2002); Solanto, Behab. Brain Res., 130, 65 (2002);Swanson et al., Behab. Brain Res., 130, 73 (2002)); and depression,anxiety, and stress disorders (see Wall et al., Prog.Neuropsychopharmacol. Biol. Psychiatry, 27, 395 (2003); Laasko et al.,Am. J. Psychiatry, 160, 904 (2003); Lawford et al., Eur.Neuropsychopharmacol., 13, 313 (2003); Buller et al.,Psychoneuroendocrinology, 28, 715 (2003); Brunswick et al., Am. J.Psychiatry, 160, 1836 (2003); Kondo et al., Prog. Neuropsychopharmacol.Biol. Psychiatry, 27, 921 (2003).

In a further embodiment, the present invention provides a method ofincreasing attention to stimuli in the environment relative to anuntreated control in a mammal comprising administering to the mammal aneffective amount of a benztropine compound of the formula (III):

in which R¹ is C₁-C₁₂ alkyl or C₂-C₁₂ alkenyl; and R² and R³ are eachindependently hydrogen or halo. Such method is useful in the treatmentof ADHD. Preferably, R¹ is methyl and R² and R³ are fluoro.

Also provided is a method of reducing the effect of nicotine by at least50% in a mammal comprising administering to the mammal an effectiveamount of a benztropine compound of the formula (III):

in which R¹ is C₁-C₁₂ alkyl or C₂-C₁₂ alkenyl; and R² and R³ are eachindependently hydrogen or halo. Such method is useful for treatingnicotine and/or tobacco addiction. Preferably, R¹ is methyl, allyl, orbutyl, and R² and R³ are fluoro.

In yet another embodiment, the invention provides a method of reducingfood intake in a mammal comprising administering to the mammal aneffective amount of a benztropine compound of the formula (III):

in which R¹ is C₁-C₁₂ alkyl or C₂-C₁₂ alkenyl; and R² and R³ are eachindependently hydrogen or halo. Such method is useful in the treatmentof weight disorders, including obesity. Preferably, (a) R¹ is methyl,allyl, or butyl, and R² and R³ are fluoro; or (b) R¹ is methyl, R² ischloro, and R³ is hydrogen.

The benztropine compounds of Formula III can be prepared by any suitablemethod, for example, by using the synthetic schemes set forth in U.S.Pat. No. 5,792,775.

In another aspect, the present invention provides a method of treating apatient for a mental disorder, the method comprising administering tothe patient a therapeutically effective amount of a compound of FormulaI-III. It will be appreciated that the compositions and methods of theinvention do not require that the compound of Formula I be present in anenantiomerically pure form (i.e., all compounds having the substituentR⁴ in the (-position), rather the compositions and methods of theinvention can comprise the compound of Formula I in racemic form.Preferably, the compound of Formula II or III is present in at leastabout 5% ee, about 10% ee, about 20% ee, about 30% ee, about 40% ee,about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, orabout 100% ee.

“Treatment” or “treating,” as used herein, refer to any administrationof a compound of the present invention and include: (i) inhibiting thesymptoms of the mental disorder, e.g., cocaine addiction; and/or (ii)lessening or inhibiting the long term effects of the mental disorder,e.g., cocaine addiction. In therapeutic applications, compositions areadministered to a patient already suffering from the mental disorder,e.g., cocaine addiction, in an amount sufficient to cure or at leastpartially arrest or alleviate the symptoms of the mental disorder and/orits complications. An amount adequate to accomplish this is defined as a“therapeutically effective” amount or dose. Amounts effective for thisuse will depend on the severity and course of the mental disorder,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In conjunction with the foregoing method, the present invention providespharmaceutical compositions comprising a compound of any of FormulaI-III and a pharmaceutically acceptable carrier, diluent, or excipient.The phrase “pharmaceutically or therapeutically acceptable carrier,” asused herein, refers to a carrier medium which does not interfere withthe effectiveness of the biological activity of the active ingredientsand which is not toxic to the host or patient. The pharmaceuticalcompositions of the present invention can be in a variety of forms.These include, for example, solid, semi-solid and liquid dosage forms,such as tablets, pills, powders, liquid solutions or suspensions,liposomes, injectable and infusible solutions. Inhalable preparations,such as aerosols, are also included. Preferred formulations are thosedirected to oral, intranasal and parenteral applications, but it will beappreciated that the preferred form will depend on the particulartherapeutic application at hand. The methods for the formulation andpreparation of therapeutic compositions comprising the compounds of theinvention are well known in the art and are described in, for example,REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Company,Philadelphia, Pa., 17th ed. (1985)), THE MERCK INDEX 11th Ed., (Merck &Co. 1989), and Langer, Science, 249, 1527-1533 (1990).

The pharmaceutical compositions containing the compounds of the presentinvention can be administered for therapeutic and/or prophylactictreatments. In therapeutic applications, compositions are administeredto a patient already suffering from a mental disorder, e.g., cocaineaddiction or Parkinson's disease, in an amount sufficient to cure or atleast partially arrest the symptoms of the mental disorder and itscomplications.

In prophylactic applications, the pharmaceutical compositions areadministered to a patient susceptible to or otherwise at risk for aparticular disease in an amount sufficient to prevent or ameliorate theonset of symptoms. Such an amount is defined as a “prophylacticallyeffective amount or dose.” These can be administered orally or byinhalation. In this use, the precise amounts again depend on thepatient's state of health, weight, and the like.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved condition is retained.When the symptoms have been alleviated to the desired level, treatmentcan cease. Patients can, however, require intermittent treatment on along-term basis upon any recurrence of the mental disorder symptoms.

In general, a suitable effective dose of the compounds of the presentinvention will be in the range of 0.05 to 1000 milligram (mg) perrecipient per day, preferably in the range of 0.1 to 100 mg per day. Thedesired dosage is preferably presented in one, two, three, four or moresubdoses administered at appropriate intervals throughout the day. Thesesubdoses can be administered as unit dosage forms, for example,containing 0.01 to 1000 mg, preferably 0.01 to 100 mg of activeingredient per unit dosage form. Again, the desired dosage will dependon, for example, the particular compound employed, the mental disorderto be treated, the manner of administration, the weight and generalstate of health of the patient, and the judgment of the prescribingphysician.

While it is possible to administer the active ingredient of thisinvention alone, it is preferable to present it as part of apharmaceutical formulation. The formulations of the present inventioncomprise at least one compound described herein in a therapeutically orpharmaceutically effective dose together with a pharmaceuticallyacceptable carrier. For parenteral administration, for example, thepharmaceutical compositions comprise a solution of a compound of FormulaI, as described above, dissolved or suspended in an acceptable carrier,preferably an aqueous carrier. A variety of aqueous carriers can be usedincluding, for example, water, buffered water, 0.4% saline, 0.3%glycine, hyaluronic acid and the like. These compositions may besterilized by conventional, well known sterilization techniques or, theymay be sterile filtered. The resulting aqueous solutions may be packagedfor use as is or lyophilized, the lyophilized preparation being combinedwith a sterile solution prior to administration. The compositions maycontain pharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions including pH adjusting andbuffering agents, tonicity adjusting agents, wetting agents and thelike, such as, for example, sodium acetate, sodium lactate, sodiumchloride, potassium chloride, calcium chloride, sorbitan monolaurate,triethanolamine oleate, etc.

For solid compositions, conventional nontoxic solid carriers may be usedwhich include, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. For oraladministration, a pharmaceutically acceptable nontoxic composition isformed by incorporating any of the normally employed excipients, such asthose carriers previously listed, and generally about 10% to about 95%of the active ingredient and, more preferably, about 25% to about 75% ofthe active ingredient.

For aerosol administration, the compounds of Formula I-V are preferablysupplied in a finely divided form along with a surfactant andpropellant. The surfactant must, of course, be nontoxic, and preferablysoluble in the propellant. Representative of such agents are the estersor partial esters of fatty acids containing from 6 to 22 carbon atoms,such as caproic, octanoic, lauric, palmitic, stearic, linoleic,linolenic, olesteric and oleic acids with an aliphatic polyhydricalcohol or its cyclic anhydride. Mixed esters, such as mixed or naturalglycerides may be employed. A carrier can also be included as desired,as with, e.g., lecithin, for intranasal delivery.

In addition to the foregoing, the benztropine analogs of the presentinvention are useful as imaging probes for dopamine transporter/cocainebinding sites and as imaging probes for neurodegenerative disorders(e.g., Parkinson's disease). As such, in another aspect, the presentinvention provides a method of selectively imaging cocaine binding sitesof the central nervous system of a human, the method comprising: (a)administering to the central nervous system of the patient a compoundhaving the Formula I; and (b) detecting the binding of that compound tothe central nervous system tissue.

In yet another aspect, the present invention provides a method ofdetecting or monitoring Parkinsonism in a patient, the methodcomprising: (a) administering to the human a detectably labeled compoundhaving the Formula I; and (b) detecting the binding of that compound tothe central nervous system tissue. Using this method, one can diagnoseand/or monitor Parkinson's disease, a neurological disordercharacterized by the progressive degeneration of dopamine nerveterminals.

The previous discussion pertaining to various embodiments includingpreferred embodiments of benztropine analogs as compounds per se isapplicable to the benztropine analogs used in the method of imagingcocaine binding sites and in the methods of diagnosing/monitoringParkinsonism and, thus, they will not be repeated herein. In anembodiment, the benztropine analogs of the present invention are labeledwith a radioactive or fluorescent label using standard labelingtechniques known to and used by those of skill in the art. Suitablelabels include, but are not limited to ¹¹C on the N-linked R¹substituent; ¹²³I, ⁷⁶Br or ¹⁸F, in an embodiment, on thephenylarylmethyl group attached to O; and ⁹⁹Tc on the phenylarylmethylgroup attached to O.

In addition, in an embodiment, binding of the benztropine analogs to theCNS tissue is detected using positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT). PET imaging may becarried using any appropriate apparatus, but is preferably carried outusing coded single ring positron tomograph (Brownell et al., Intl. J.Imaging Syst. Tech., 1, 207-217, 1989). The analog ring design offers anumber of advantages for positron tomography. PET imaging can be carriedout on conscious human subjects. In addition, SPECT imaging may also beused on human subjects (See, e.g., Medicine, Scientific American, Inc.,ed. Rubenstein and Federman, 1988; Jaszczak and Coleman, Invest.Radiol., 20, 897, 1985; and Coleman, et al., Invest. Radiol., 21, 1,1986); preferably SPECT imaging employs gamma-emitting derivatives ofthe analogs described herein (e.g., benztropine analogs labeled with¹²³I or ⁹⁹Tc).

As such, using the benztropine analogs of the present invention, one can(1) assay cocaine receptors in chronic cocaine users and in individualsexposed to cocaine prenatally, (2) assay the receptor occupancy ofpotential cocaine therapeutics, (3) assay cocaine receptors inindividuals that abuse other drugs, (4) investigate the mechanism bywhich cocaine and related drugs alter behavior, (5) elucidate thereceptor properties of the dopamine transporter receptor complex, (6)study the mechanism of dopamine transport, etc. Thus, the benztropineanalogs of the present invention are useful, inter alia, in research,e.g., in in vivo and in vitro experiments, to study dopamine transport,the dopamine transport receptor and, in particular, cocaine bindingsites.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are intended neither to limit nor define the invention in anymanner.

EXAMPLES

General Methodology. All chemicals and reagents were purchased fromAldrich Chemical Co. or Lancaster Synthesis, Inc., and used withoutfurther purification. All melting points were determined on aThomas-Hoover melting point apparatus and are uncorrected. The ¹H and¹³C NMR spectra were recorded on Bruker AC-300 or a Varian Mercury Plus400 instruments. Proton chemical shifts are reported as parts permillion (8 ppm) relative to tetramethylsilane (0.00 ppm) as an internalstandard. Coupling constants are measured in Hertz. Chemical shifts for¹³C NMR spectra are reported as 8 relative to deuterated chloroform(CDCl₃, 77.5 ppm, CD₃OD 49.3). Infrared spectra were recorded as a neatfilm on NaCl plates with a Perkin-Elmer Spectrum RX I FT-IR system.Microanalyses were performed by Atlantic Microlab, Inc. (Norcross, Ga.)and agree with ±0.4% of calculated values. All column chromatography wasperformed using the silica gel (Merck, 230-400 mesh, 60 Å) andCHCl₃/CH₃OH 10:1) as eluting solvent unless otherwise indicated. If nototherwise stated all spectroscopic data and yields refer to the freebase.

S-(+)-2β-hydroxymethyl-3α-[bis(4-fluorophenyl)methoxy]tropane (2). Asolution of 1a or 1b (3.03 mmol) in 8 mL of ether at 0° C. was addeddropwise to a suspension of LiAlH₄ (115 mg, 3.03 mmol) in dry ethylether (8 mL). After the addition, the ice-H₂O bath was removed and thereaction mixture was allowed to warm to room temperature for 3 h. H₂O(0.3 mL) was added carefully at 0° C., followed by the addition of 0.5mL of aqueous NaOH (2N). The resulting mixture was filtered, and thefiltrate was dried (K₂CO₃). Ether was removed, and the residue waspurified by flash column chromatography (eluting with 5-10%(CHCl₃/NH₄OH; CMA) to give the product (1.02 g, 90%) as a colorless anoil. [α]^(D) ₂₅+37.5° (c=1.0, CHCl₃); ¹H NMR (CDCl₃) α 2.14-1.79(m, 7H),2.22(s, 3H), 3.12(m, 1H), 3.24(m, 1H), 3.46(dd, J=2.8, 10.4 Hz, 1H),3.56(d, J=6.0 Hz, 1H), 3.93(dd, J=2.4, 10.0Hz, 1H), 5.38(s, 1H), 6.98(m,4H), 7.22(m, 4H), ppm.

S-(+)-2β-Formyl-3α-[bis(4-fluorophenyl)methoxy]tropane (3). To asolution of oxalyl chloride (1.64 mL, 2. 0 M solution in CH₂Cl₂, 3.28mmol) under argon at −78° C. was added a solution of DMSO (469 mg, 6.02mmol) in dry CH₂Cl₂ (1 mL). After 0.5 h, a solution of the alcohol 2(1.02 g, 2.73 mmol) in dry CH₂Cl₂ (3 mL) was added and the reactionmixture was stirred for 1 h at −78° C., followed by addition oftriethylamine (1.71 mL, 12.3 mmol) at the same temperature. The reactionmixture was then allowed to warm to room temperature and diluted withH₂O (20 mL). The organic layer was separated and the aqueous layer wasextracted with CH₂Cl₂ (3×20 mL). The combined organic layers were dried(K₂CO₃) and concentrated to yield the aldehyde (994 mg, 98%). ‘H NMR(CDCl₃) 8 2.21-1.58(m, 7H), 2.23(s, 3H), 3.06(m, 1H), 3.57(m, 1H),3.99(m, 1H), 5.37(s, 1H) 6.98(m, 4H), 7.24(m, 4H), 9.59(s, 1H), ppm. Thealdehyde (3) was used in the following steps without furtherpurification.

S-(+)-2β-Ethenyl-3α-[bis(4-fluorophenyl)methoxy]tropane (4). To asuspension of methyltriphenylphosphonium bromide (195 mg, 0.55 mmol) indry tetrahydrofuran (THF) (3 mL) was added dropwise butyllithium (0.22mL, 2.5 M solution in hexane, 0.55 mmol) at 0° C. under argon. Theresulting yellow-orange solution was stirred for 30 min, and the ice-H₂O bath was then removed. The crude aldehyde (169 mg, 0.46mmol) in 2 mLof THF was added, and the reaction mixture was stirred overnight at roomtemperature. The mixture was diluted with H₂O (20 mL), and the twolayers were separated. The aqueous layer was extracted with CHCl₃ (3×20mL). The combined organic layers were dried (K₂CO₃) and concentrated.The residue was purified by column chromatography to afford the product(105 mg, 62%) as an oil. IR: 1222 cm⁻¹; ¹HNMR (CDCl₃) α 2.08-1.75(m.6H), 2.21(s, 3H), 2.47(m, 1H), 2.99(m, 1H), 3.07(m, 1H), 3.32(d, J=5.2Hz, 1H), 4.88(d, J=17.2 Hz, 1H), 4.96(d, J=10.4 Hz, 1H), 5.37(s, 1H),5.96(m, 1H), 6.98(m, 4H), 7.30(m, 4H), ppm; ¹³C NMR δ 24.9, 25.4, 36.1,42.0, 50.1, 60.6, 65.9, 74.0, 79.8, 114.1, 115.1, 115.3, 128.3, 128.5,138.5, 140.9, 160.8, 163.3, ppm.

S-(+)-2β-(2′-(methoxycarbonyl)eth-1′-enyl)-3α-[bis(4-fluorophenyl)methoxy]tropane(5). To a suspension of LiCl (80 mg, 1.89 mmol) in dry acetonitrile (8mL) at room temperature under an argon atmosphere were added trimethylphosphonoacetate (343 mg, 1.89 mmol), N,N-diisopropylethylamine (203 mg,1.57mmol), and the aldehyde (3, 583 mg, 1.57 mmol). The reaction mixturewas allowed to stir for 24 h, acetonitrile was then removed underreduced pressure. The residue was diluted with H₂O (20 mL) and extractedwith CHCl₃ (3×20 mL). The combined organic layers were dried (K₂CO₃) andconcentrated. The crude product was purified by column chromatography(3% CMA) to afford the product (580 mg, 86%) as a light yellow solid. ¹HNMR (CDCl₃) α 2.16-1.78(m, 6H), 2.20(s, 3H), 2.58(d, J=8.0 Hz, 1H),3.12-3.00(m, 2H), 3.34(d, J=6.0 Hz, 1H), 3.70(s, 3H), 5.35(s, 1H),5.68(dd, J=1.2, 16 Hz, 1H), 7.08-6.97(m, 5H), 7.24(m, 4H), ppm; ¹³C NMRδ 25.4, 25.9, 36.4, 42.3, 49.4, 51.8, 60.9, 65.4, 73.6, 80.4, 115.5,115.7, 120.8, 128.5, 128.6, 138.3, 151.0, 161.0, 163.4, 167.2, ppm;GC-MS(m/z) 427(M+).

S-(+)-2β-(2′-(Methoxycarbonypethyl)-3α-[bis(4-fluorophenyl)methoxy]tropane(6). A teaspoon of Raney Ni (in H₂O ) was placed in a Parr bottle andwashed (×3) with MeOH. The unsaturated compound 5 (580 mg, 1.36mmol) inMeOH (40 mL) was added and the mixture was hydrogenated (40 psi) for 1.5h. GC-MS showed the complete absence of starting material. The reactionmixture was then filtered and the solvents were evaporated under reducedpressure. The residue was purified by chromatography (Et₂O/Et₃N=95/5) togive (510 mg. 87.5%) as an oil. ¹H NMR (CDCl₃) α 2.06-1.48(m, 9H),2.17(t, J=Hz, 2H), 2.21(s, 3H), 2.94(m, 1H), 3.03(m, 1H), 3.16(d, J=5.2Hz, 1H), 3.66(s, 3H), 5.34(s, 1H), 6.99(m, 4H), 7.25(m, 4H), ppm; ¹³CNMR δ 24.8, 25.9, 28.3, 32.6, 35.9, 42.4, 45.6, 51.9, 61.3, 65.3, 73.1,79.7, 115.4, 115.6, 128.5, 128.6, 138.6, 138.7, 160.9, 163.3, 174.1,ppm; GC-MS(m/z) 429(M+).

S-(+)-2β-{[4-(4′-Nitrophenyl)butyryl]oxymethyl}-3α-[bis(4-fluorophenyl)methoxy]tropane (7). 4-(4′-Nitrophenyl)butyric acid (414 mg, 1.98 mmol)in SOCl₂ (8 mL) was refluxed for 3 h. Excess of SOCl₂ was removed, andthe residue was dissolved in CH₂Cl₂ (20 mL). To the solution was addedalcohol 2 (492 mg, 1.32 mmol), followed by the slow addition oftriethylamine (1.1 mL, 7.9 mmol) at 0° C. The reaction mixture was thenallowed to stir at room temperature for 3 h. The mixture was dilutedwith H₂O (30 mL), and the two layers were separated, the aqueous layerwas further extracted with CH₂Cl₂ (3×20 mL). The combined organic layerswere dried (K₂CO₃) and concentrated. The residue was purified by columnchromatography (eluting with Et₂O/Et₃N=97/3) to give the product (644mg, 87%) as a brown oil. [α]^(D) ₂₅+3.5° (c=1.0, CHCl₃); ¹H NMR (CDCl₃)α 2.08-1.62(m, 11H), 2.15(s, 3H, N—CH3), 2.72(t, J=7.6 Hz, COCH2),3.07-2.98 (m, 2H), 3.30(d, J=5.2 Hz, 1H), 4.00(dd, J=9.2, 11.2 Hz, 1H,CH₂O), 4.09(dd, J=6.0, 11.2 Hz, 1H, CH₂O), 5.34(s, 1H, OCHAr₂), 6.96(m,4H, Ar—H), 7.24(m, 4H, Ar—H), 7.32(d, J=8.8 Hz, 2H, Ar—H), 8.15(d, J=8.8Hz, 2H, Ar—H), ppm; ¹³C NMR δ 24.2, 25.5, 25.9, 33.3, 34.9, 35.4, 45.8,60.8, 62.8, 66.2, 70.1, 79.4, 115.1, 115.3, 123.7, 128.3, 128.4, 129.2,138.4, 146.5, 149.2, 160.8, 163.2, 172.8, ppm; Anal. (C₃₂H₃₄N₂F₂O₅) forC, H, N.

S-(−)-2β-{[4-(4′-Aminophenyl)butyryl]oxymethyl}-3α-[bis(4-fluorophenyl)methoxy]tropane(8). A teaspoon of Raney Ni (in H₂O) was placed in a Parr bottle andwashed (×3) with . To this were added the nitro compound MFZ 6-83 and/EtOAc (mL/mL). The mixture was hydrogenated at 30 psi overnight. Thinlayer chromatography showed all the absence of starting material. Themixture was then filtered, and the filtrate was concentrated. Theresidue was purified by column chromatography (5% CMA) to give theproduct as an oil. [α]^(D) ₂₅−5.4° (c=1.0, CHCl₃); IR: 1727, 1603, 1221,cm⁻¹; ¹H NMR (CDCl₃) α 2.18-1.63(m, 11H), 2.15(s, 3H), 2.51(t, J=7.6 Hz,2H), 3.07-2.98(m, 2H), 3.30(d, J=5.2 Hz, 1H), 3.70-3.40(brs, 2H, NH2),3.95(dd, J=9.2, 11.0 Hz, 1H), 4.10(dd, J=6.0, 11.0 Hz, 1H), 5.32(s, 1H),6.63(d, J=8.8 Hz, 2H), 6.96(m, 6H), 7.22(m, 4H), ppm; ¹³C NMR δ 24.6,25.7, 27.0, 33.8, 34.5, 35.9, 42.1, 45.8, 61.1,63.0, 66.2, 70.4, 79.6,115.3, 115.5, 128.6, 128.7, 129.5, 131.6, 138.6, 144.7, 161.0, 163.4,173.7, ppm.

S-(−)-2β-{[4-(3′-iodo-4′-Aminophenyl)butyryl]oxymethyl}-3α-[bis(4-fluorophenyl)methoxy]tropane.Compound 8 (115 mg, 0.22 mmol) was dissolved in acetic acid (4 mL). Tothe solution was added extremely slowly ICI (42 mg, 0.26 mmol) in aceticacid (2 mL) over 3 h. After the addition, the solvent was removed underreduced pressure. The residue was then diluted with H₂O (10 mL),basified with NaHCO₃, and extracted with CHCl₃ (3×10 mL). The combinedorganic layers were dried (K₂CO₃) and concentrated. The residue waspurified by column chromatography (eluent: Et₂O/Et₃N=97:3) to afford theproduct (45 mg, 32%) as an oil. [α]^(D) ₂₅−5.4° (c=1.0, CHCl₃); IR:1728, 1603, 1221, cm⁻¹; ¹H NMR (CDCl₃) α 2.18-1.70(m, 11H), 2.16(s, 3H),2.47(t, J=7.6 Hz, 2H), 3.09-2.98(m, 2H), 3.31(d, J=4.8 Hz, 1H),4.02-3.90(m, 3H), 4.09(dd, J=6.0, 11.2Hz, 1H), 5.33(s, 1H), 6.68(d,J=7.6 Hz, 1H), 6.97(m. 5H), 7.23(m, 4H), 7.46(s, 1H), ppm; ¹³C NMR δ24.6, 25.7, 26.8, 33.6, 33.9, 35.9, 42.1, 45.8, 61.1, 63.0, 66.3, 70.4,79.6, 84.5, 114.9, 115.3, 115.5, 128.6, 128.7, 129.7, 133.3, 138.6,138.8, 145.1, 161.0, 163.5, 173.5, ppm.

S-(+)-N-nor-2β-Carboethoxy-3α-[bis(4-fluorophenyl)methoxy]tropane (9).Compound 1b (652 mg, 1.57 mmol) was dissolved in 1,2-dichloroethane. Tothe solution was added 1-chloroethyl chloroformate (ACE-Cl, 0.68 mL,6.28 mmol) and Na₂CO₃ (833 mg, 7.85 mmol), and the mixture was warmed toreflux for 3 h. Thin layer chromatography (TLC) showed the startingmaterial disappeared. After cooling to room temperature, the reactionmixture was filtered. Solvent in the filtrate was removed. The residuewas then dissolved in MeOH (20 mL), and the solution was then refluxedfor 1 h. Methanol was removed in vacuo. The residue was diluted with H₂O(50 mL), basified with NaHCO₃, and extracted with CHCl₃ (3×50 mL). Thecombined organic layer was dried (K₂CO₃) and concentrated. The residuewas purified by column chromatography (eluting with 5% CMA) to give theproduct (610 mg, 97%) as an oil. [α]^(D) ₂₅+33.8° (c=1.0, CHCl₃); IR:3326, 1728, 1212, cm⁻¹; ¹H NMR (CDCl₃) α 1.23(t, J=7.2 Hz, 3H),1.97-1.65(m, 5H), 2.22-2.06(m, 2H), 2.65(s, 1H), 3.48(m, 1H0, 3.79(m,1H), 3.83(d, (J=Hz, 1H), 4.17-4.04(m, 2H), 5.37(s, 1H), 7.00(dd, J=Hz,4H), 7.25(m, 4H), ppm; ¹³C NMR δ 14.6, 28.9, 29.2, 36.0, 50.6, 53.5,55.8, 51, 71.2, 80.6, 115.4, 115.6, 128.5, 128.7, 138.3, 161.0, 163.4,173.2, ppm; GC-MS(m/Z) 401(M+).

S-(+)-N-Allyl-2β-carboethoxy-3α-[bis(4-fluorophenyl)methoxy]tropane(11). Compound 9 (85 mg, 0.21 mmol) and allyl bromide (51 mg, 0.42 mmol)were combined in dimethylformamide (DMF) (3 mL). To the solution wasadded K₂CO₃ (58 mg, 0.42 mmol), and the mixture was heated to 65° C.overnight. H₂O (20 mL) was added, and the mixture was extracted withCHCl₃ (3×30 mL). The combined organic layer was dried (K₂CO₃) andconcentrated. The residue was purified by column chromatography (elutingwith 3% CMA) to give the product (86 mg, 92%) as an oil. ¹H NMR (CDCl₃)α 1.23(t, J=7.2 Hz, 3H), 2.18-1.58(m, 6H), 2.69(m, 1H), 2.81(dd, J=7.2,13.6 Hz, 1H), 2.94(dd, J=5.6, 13.6 Hz, 1H), 3.15(m, 1H), 3.68(m, 1H),4.00(d, J=2.0 Hz, 1H), 4.18-4.02(m, 2H), 5.12-5.02(m, 2H), 5.34(s, 1H),5.78(m, 1H), 6.98(m, 4H), 7.25(m, 4H), ppm; ¹³C NMR δ 14.2, 24.6, 25.9,36.3, 51.8, 56.7, 59.8, 60.2, 60.4, 70.7, 80.3, 115.2, 115.4116.3,128.3, 128.4, 136.8, 138.3, 138.4, 160.8, 163.3, 172.5, ppm.

S-(+)-N-Butyl-2β-carboethoxy-3α-[bis(4-fluorophenyl)methoxy]tropane(10). Compound 10 was obtained in 87% yield by the procedure describedabove for compound 11 using butyl bromide. [α]^(D) ₂₅+20.4° (c=1.0,CHCl₃); IR: 1729, 1603, 1223, cm⁻¹; ¹H NMR (CDCl₃) α 0.86(t, J=7.2 Hz,3H), 1.24(t, J=7.2Hz, 3H), 1.40-1.20(m. 4H), 2.21-1.74(m, 8H), 2.68(m,1H), 3.12(m, 1H), 3.69(m, 1H), 3.99(d, J=4.8 Hz, 1H), 4.09(m, 2H),5.34(s, 1H), 6.98(m, 4H), 7.23(m, 4H), ppm; ¹³C NMR δ 14.3, 14.4, 20.7,24.9, 26.2, 31.5, 36.5, 52.1, 53.5, 60.6, 60.7, 61.0, 71.1, 80.5, 110.0,115.4, 115.6, 128.5, 128.6, 138.8, 161.0, 163.5, 172.7, ppm.

S-(+)-2β-Carbomethoxy-3α-[bis(4-chlorophenyl)methoxy]tropane (14).S-(+)-alloecgonine methyl ester (Zou et al., J. Med. Chem., 46,2908-2916 (2003)) (309 mg, 1.55 mmol), 4,4′-dichlorobenzhydrol (786 mg,3.10 mmol), p-toluenesulfonic acid monohydrate (443mg, 2.33 mmol), andbenzene (15 mL) were placed in a 50 mL round-bottom flask fitted with aDean-Stark trap and condenser. The reaction mixture was heated to refluxfor 24 h. The solvent was then removed, and the residue was diluted withwater (20 mL), basified with NH₄OH to pH 9, and extracted with CHCl₃(3×20 mL). The combined organic layer was dried (K₂CO₃) andconcentrated. The residue was purified by column chromatography(CHCl₃/NH₄OH, 97:3:1) to afford S-(+)-14 (472 mg, 70%) as an oil, whichsolidified slowly to a white solid after standing at room temperature.Mp: 109-110° C. (lit. mp (Meltzer et al., J. Med. Chem., 39, 371-379(1996)): 110-112° C.). [α]D25+17.30 (c=1.0, CHCl₃); IR: 1732, 1069,cm⁻¹; 1H NMR (CDCl₃) α 2.17-1.68 (m, 6H), 2.18 (s, 3H), 2.71 (m, 1H),3.09 (m, 1H), 3.59 (m, 1H), 3.68(s, 3H), 3.95 (d, J=4.8 Hz, 1H), 5.32(s, 1H), 7.30-7.12 (m, 8H), ppm; GC-MS (m/z) 433(M+); Anal.(C₂₃H₂₅NCl₂O₃) for C,H,N.

(±)-14 was prepared by the same procedure in 75% yield. Mp: 108-110° C.The IR, 1H NMR, and GC-MS spectra for (±)-14 were identical to S-(+)-14.Anal. (C₂₃H₂₅NCl₂O₃) for C,H,N.

S-(+)-2β-Carboethoxy-3α-[bis(4-chlorophenyl)methoxy]tropane (15).S-(+)-15 was prepared in 78% yield according to the above procedure. Mp:88-89.5° C. [α]D24+17.00 (c=1.0, CHCl₃); IR: 1733, 1222, cm⁻¹; 1H NMR(CDCl₃) α 1.22 (t, J=7.0 Hz, 3H), 2.16-1.65 (m, 6H), 2.18 (s, 3H), 2.68(m, 1H), 3.08 (m, 1H), 3.58 (m, 1H), 3.97 (d, J=4.8 Hz, 1H), 4.22-4.00(m, 2H), 5.30 (s, 1H), 7.30-7.16 (m, 8H), ppm; GC-MS (m/z) 447 (M+);anal. (C₂₄H₂₇NCl₂O₃) for C,H,N.

(±)-15 was prepared in 74% yield by the same procedure. Mp: 87.5-89.5°C. The IR, 1H NMR, and GC-MS spectra for (±)-15 were identical toS-(+)-15. Anal. (C₂₄H₂₇NCl₂O₃) for C,H,N.

Dopamine Transporter Binding Assay. Male Sprague-Dawley rats (200-250 g,Taconic, Germantown, N.Y.) were decapitated and their brains removed toan ice-cooled dish for dissection of the caudate putamen. The tissue washomogenized in 30 volumes of ice-cold modified sucrose using a Brinkmanpolytron and centrifuged at 20,000×g for 10 min at 4° C. The resultingpellet was then washed two more times by re-suspension in ice-coldbuffer and centrifugation at 20,000×g for 10 min at 4° C. Freshhomogenates were used in all experiments.

Binding assays were conducted in modified sucrose buffer on ice. Thetotal volume in each tube was 0.5 mL and the final concentration ofmembrane after all additions was 0.5% (w/v) corresponding to 200-300 mgof protein/sample. Triplicate samples of membrane suspension werepreincubated for 5 min in the presence or absence of the compound beingtested. [³H]WIN 35,428 (2-β-carbomethoxy-3-(-(4-fluorophenyl)tropane1,5-naphthalene disulfonate; specific activity 82.4 C_(i)/mmol, from NewEngland Nuclear, Boston, Mass., final concentration 1.5 nM) was addedand the incubation was continued for 1 hr on ice. The incubation wasterminated by the addition of 3 mL of ice-cold buffer and rapidfiltration through Whatman GF/B glass fiber filter paper (presoaked in0.1% bovine serum albumin (BSA) in water to reduce non-specific binding)using a Brandel Cell Harvester (Gaithersburg, Md.). The filters werewashed with three additional 3 mL washes and transferred toscintillation vials. Absolute ethanol (0.5 mL) and Beckman Ready ValueScintillation Cocktail (2.75 mL) were added to the vials which werecounted the next day at an efficiency of about 36%. Under these assayconditions, an average experiment yielded approximately 6,000 dpm totalbinding per sample, and approximately 250 dpm non-specific binding,defined as binding in the presence of 100 μM cocaine. Each compound wastested with concentrations ranging from 0.01 nM to 100 μM forcompetition against binding of [³H]WIN 35,428, in three independentexperiments, each performed in triplicate.

Saturation and displacement data were analyzed by the use of thenonlinear least squares curve-fitting computer program PRISM. Data fromreplicate experiments were modeled together to produce a set ofparameter estimates and the associated standard errors of theseestimates. In each case, the model reported fit significantly betterthan all others according to the F test at p<0.05. The K, valuesreported are the dissociation constants derived for the unlabeledligands.

³H]Nisoxetine Binding Assay. Membranes from frozen frontal cortexdissected from male Sprague-Dawley rats (Taconic Labs, Germantown, N.Y.)were homogenized in 20 volumes (w/v) of 50 mM Tris containing 120 mMNaCl and 5 mM KCl (pH 7.4 at 25° C.), using a Brinkman Polytron (atsetting 6 for 20 sec). The tissue was centrifuged at 50,000×g for 10 minat 4° C. The resulting pellet was resuspended in buffer andrecentrifuged. The final pellet was resuspended in cold buffer to aconcentration of 80 mg/mL (original wet weight). Ligand bindingexperiments were conducted in assay tubes containing 0.5 mL buffer, 0.5nM [³H]nisoxetine (New England Nuclear, Boston Mass.), and 8 mg frontalcortex tissue. The reaction was started with the addition of the tissueand the tubes were incubated for 60 min at 0-4° C. The incubation wasterminated by rapid filtration through Whatman GF/B filters, presoakedin 0.05% polyethylenimine, using a Brandel Cell Harvester (BrandelInstruments Gaithersburg, Md.). The filters were washed twice with 5 mLcold buffer, transferred to scintillation vials to which Beckman ReadySafe was added. Nonspecific binding was determined using 1 μMdesipramine. Data were analyzed using GraphPad Prism software (SanDiego, Calif.).

[³H]Citalopram Binding Assay. Membranes from frozen rat midbrain werehomogenized in 20 volumes (w/v) of 50 mM Tris containing 120 mM NaCl and5 mM KCl (pH 7.4 at 25° C.), using a Brinkman Polytron (at setting 6 for20 sec). The tissue was centrifuged at 20,000×g for 10 min at 4° C. Theresulting pellet was resuspended in buffer and recentrifuged. The finalpellet was resuspended in cold buffer to a concentration of 15 mg/mL(original wet weight). Ligand binding experiments were conducted inassay tubes containing 0.5 mL of buffer, 1.4 nM [³H]citalopram (NewEngland Nuclear, Boston Mass.), and 1.5 mg midbrain tissue. The reactionwas started with the addition of the tissue and the tubes were incubatedfor 60 min at 25° C. (room temperature). The incubation was terminatedby rapid filtration through Whatman GF/B filters (presoaked in 0.3%polyethylenimine in water) using a Brandel Cell Harvester (BrandelInstruments Gaithersburg, Md.). The filters were washed twice with 5 mLcold buffer, transferred to scintillation vials to which Beckman ReadySafe was added. Nonspecific binding was determined using 10 μMfluoxetine (RBI, Natick, Mass.). Data were analyzed using GraphPad Prismsoftware (San Diego, Calif.).

[³H]Pirenzepine Binding Assay. Membranes from frozen rat brainsexcluding cerebellum were thawed in ice-cold buffer (10 mM Tris-HCl, 320mM sucrose, pH 7.4) and homogenized with a Brinkman polytron in a volumeof 10 mL/μm of tissue. The homogenate was centrifuged at 1,000×g for 10min at 4° C. The resulting supernatant was then centrifuged at 10,000×gfor 20 min at 4° C. The resulting pellet was resuspended in a volume of200 mg/mL in 10 mM Tris buffer (pH 7.4). Ligand binding assays wereconducted in tubes containing 0.5 mL of buffer (10 mM Tris-HCl, 5 mMMgCl₂), 3 nM [³H]pirenzepine (New England Nuclear, Boston, Mass.), and20 mg of brain tissue. The reaction was started with the addition of thetissue and the tubes were incubated for 60 min in a 37° C. water bath.The incubation was terminated by the addition of 5 mL of ice-cold buffer(10 mM Tris-HCl, pH 7.4) and rapid filtration through Whatman GF/B glassfiber filter paper (presoaked in 0.5% polyethylenimine) using a BrandelCell Harvester (Brandel Instruments, Gaithersburg, Md.). The filterswere washed twice with 5 mL cold buffer, and transferred toscintillation vials to which absolute ethanol and Beckman Ready Safe wasadded. Quinuclidinyl benzilate (QNB), 100 μM final concentration, wasused to determine non-specific binding. Data were analyzed by usingGraphPad Prism software (San Diego, Calif.).

Dopamine Uptake Assay. The tissue was homogenized in ice cold buffer (5mM HEPES, 0.32M sucrose) using 10 strokes with a Teflon glasshomogenizer followed by centrifugation at 1000 g for 10 min at 4° C. Thesupernatant was saved and recentrifuged at 10,000 g for 20 min at 4° C.The supernatant was then discarded and the pellet was gently resuspendedin an ice cold incubation buffer (127 mM NaCl, 5 mM KCl, 1.3 mM NaH₂PO₄,1.2 mM MgSO₄, 2.5 mM CaCl₂, 1.498 mM HEPES acid, 10 mM D-Glucose, 1.14mM L-ascorbic acid, pH 7.4) and placed on ice for 15 min. Thesynaptosomal tissue preparation was incubated in buffer in glass testtubes at 37° C. to which 10 μM pargyline and either the drug beingtested or no drug was added, as appropriate. After a 10 minutepre-incubation in the presence of drug, [3H] dopamine (finalconcentration, 0.5 nM) (Amersham Biosciences, Piscataway, N.J.) wasadded to each tube and the incubation was carried on for 5 min. Thereaction was terminated by the addition of 3 mL ice cold buffer to eachtube and rapid filtration through Whatman GF/B glass fiber filter paper(presoaked in 0.1% polyethylenimine in water) using a Brandel cellharvester (Brandel Instruments, Gaithersburg, Md.). After filtration,the filters were washed with two additional 5 mL washes and transferredinto scintillation vials. Beckman Ready Value (Beckman-CoulterInstruments, Fullerton, Calif.) was added and the vials were counted thenext day using a Beckman 6000 liquid scintillation counter (BeckmanCoulter Instruments, Fullerton, Calif.). The reported values representspecific uptake from which nonspecific uptake was subtracted (defined asuptake in the presence of 100 μM (−)cocaine HCl). Data were analyzedusing the nonlinear regression analysis of GraphPad Prism Software, (SanDiego Calif.).

Cocaine Discrimination Assay. Rats weighing 320-350 g served assubjects. They were fed daily about 15 g of standard lab chow at least30 min after testing. Subjects were tested daily in two-leveroperant-conditioning chambers (Med Associates, Model ENV 007, St.Albans, Vt., USA) that were housed within light- and sound-attenuatingenclosures. White noise was present throughout testing to maskextraneous sounds. Ambient illumination was by a lamp in the top centerof the front panel (houselight). Levers were set 17 cm apart, with pairsof lamps (light-emitting diodes, LEDs) above each of the levers, also onthe front panel. A downward force on either lever of 0.4 N through about1 mm was defined as a response, and produced an audible click.Reinforced responses dispensed one 45-mg pellet (BioServe, FrenchtownN.J., USA) into a food tray centered between the levers on the frontpanel of the chamber. On-line experimental control and data collectionwere by computers with Med Associates interfacing equipment andoperating software (Med Associates, St. Albans, Vt.).

Subjects were initially trained to press both levers under a 20-responsefixed-ratio (FR 20) schedule of food reinforcement and to discriminateIP injections of 29 μmol/kg cocaine (10 mg/kg) from IP injections ofsaline. After cocaine injection, responses on only one lever werereinforced; after saline injection, responses on the other lever werereinforced. The assignment of cocaine- and saline-appropriate levers wascounterbalanced across rats. Immediately after injection, rats wereplaced inside the experimental chambers. A 5-min time-out period, duringwhich the houselight and LEDs were extinguished and responding had noscheduled consequences preceded the illumination of the houselight andthe LEDs. Only responses on the appropriate lever were reinforced, andresponses on the inappropriate lever reset the FR response requirement.Each food presentation was followed by a 20-sec time-out period duringwhich all lights were off, and responding had no scheduled consequences.Experimental sessions ended after 20 food presentations or 15 min,whichever occurred first. Training sessions with cocaine (C) and saline(S) injections were conducted daily 5 days per week, and ordered in adouble alternation sequence [e.g., . . . SCCS . . . ].

Testing was initiated when performances reached criteria of at least 85%appropriate responding overall and during the first FR 20 of the sessionover four consecutive sessions. Tests were conducted with differentdoses of cocaine or doses of the novel compounds. After a test session,a subject was required to meet the above performance criteria over twoconsecutive (cocaine and saline) training sessions in order to be testedagain. Repeated test sessions were conducted, with at least two trainingsessions between tests, until entire dose-effects were determined ineach subject. Test sessions were identical to training sessions, withthe exception that 20 consecutive responses on either lever werereinforced.

For each of the rats studied in the cocaine-discrimination procedure,the overall response rate and the percentage of responses occurring onthe cocaine-appropriate lever were calculated. The mean values werecalculated for each measure at each drug dose tested (FIG. 1A-F). Ifless than half of the rats responded at a particular dose, no mean valuewas calculated for percentage of cocaine-appropriate responding at thatdose. At least 20% cocaine-appropriate responding was adopted as aconservative criterion at which to assume a significant difference fromsaline; 80% or higher cocaine-appropriate responding was taken assimilar to the training dose of cocaine, and intermediate levels ofcocaine-appropriate responding were considered partial substitution. The2-substituted BZT analogues with 4′,4″-diF-substitutions fullysubstituted for cocaine, whereas the parent compound lacking a 2substituent (“AHN 1-055,” in which R⁴ is hydrogen), and the2-substituted BZT analogues with 4′,4″-diCl-substitutions did not fullysubstitute for cocaine.

Locomotor Activity. For the assessment of horizontal locomotor activity(ambulation), mice were tested alone in clear acrylic experimentalchambers (40 cm³). Around the outside of two perpendicular adjoiningwalls of the chambers were arrays of light sensitive detectors, spaced2.5 cm apart. Infrared light sources were mounted outside the opposingwalls and directed at the detectors (Omnitech Electronics, Columbus,Ohio, USA). Each interruption of a single light beam registered by thedetectors resulted in the tabulation of one horizontal activity count.Mice were injected and immediately placed in the apparatus for 8 h.Total activity count data were collected each 10 min and all data wereanalyzed using two-way analysis of variance (ANOVA) and post-hoc Tukey'sTest to determine significance of effects of individual doses atdifferent time periods (FIG. 2A-E). The duration of effects was greaterthan that typically obtained with cocaine, and that the maximalstimulation produced was generally (i) from 30 to 60 min after injectionof compound la (FIG. 2A); (ii) from 20 to 120 min after injection ofcompound 1b (FIG. 2B); (iii) from 20 to 60 min after injection ofcompound MFZ 2-74 (R′=Me; R^(2,3)═F; R⁴═CO₂-^(i)Pr) (FIG. 2C); (iv) from90 to 240 min after injection of compound 15 (FIG. 2D); and (v) from 50to 90 min after injection of compound 14 (FIG. 2E).

In vivo binding of [¹²⁵I]RTI-121. Each animal received an i.v. injectionof 2 μCi of [¹²⁵I]RTI-121. Two hours after administration of[¹²⁵I]RTI-121, the animals were sacrificed by cervical dislocation. Ineach mouse, displacement of [¹²⁵I]RTI-121 was examined by giving an i.p.injection of one of the displacers at various doses and times relativeto sacrifice. Displacement by test drugs at various doses was examinedat various times after their injection, with each data point determinedin sets of approximately six mice. Whole brains were rapidly removed andstriatum and cerebellum were dissected on ice. Following dissection,each brain region was placed into separate plastic vials (Rohren Tubes,55×12 mm), weighed and tissue radioactivity was measured using anautomated gamma counter (ICN Biomedicals, INC, Micromedic Systems,10/600 PLUS).

Regional radioactivity levels were divided by weight (gram) of thetissue (CPM/tissue weight). Specific binding was calculated asCPM/tissue weight in striatum divided by cerebellum minus 1 (S/C-1),which is based on the observation that dopaminergic transporter sitesare highly concentrated in the striatum and relatively absent in thecerebellum. These values were expressed as a percentage of specificbinding after vehicle injection. Data were analyzed using two-wayanalysis of variance (ANOVA), and a post-hoc Tukey's test was used todetermine significance of effects for individual doses at different timeperiods following IP injection of compound 1a (FIG. 3A), 1b (FIG. 3B),MFZ 2-74 (R′=Me; R^(2,3)═F; R⁴═CO₂-^(i)Pr) (FIG. 3C), 15 (FIG. 3D), and14 (FIG. 3E). Maximal displacement of [¹²⁵I]RTI-121 was (i) obtainedbetween 60 and 360 min after injection of compound 1a (FIG. 3A); (ii)obtained at some point beyond 180 min after injection of compound 1b(FIG. 3B); (iii) not obtained and would likely be obtained at some pointbeyond 3 hours after injection of compound MFZ 2-74 (FIG. 3C); (iv)obtained between 180 and 360 min after injection of compound 15 (FIG.3D); and (v) obtained at some point beyond 180 min after injection ofcompound 14 (FIG. 3E).

Model For Determining Increase in Attention. Rats were trained duringdaily sessions in a chamber which contained five holes along one wall.When a light came on behind one of the holes, the rat had 5 sec torespond by putting its nose in the hole. If it did this, a food pelletwas dispensed. Lights came on for one second randomly in time. Eachtenth “correct” response produced a food pellet. The rat had tocontinuously monitor (attend to) the lights to perform well. The resultswere measured and illustrated in FIG. 4A. The top curve shows thecorrect responses cumulatively throughout the session. The shortdiagonal marks on the line indicate the occasions on which food pelletswere delivered. The bottom curve shows the incorrect responsescumulatively throughout a 40 min test session. As seen in FIG. 4A,without any sort of treatment, the number of incorrect responses wasalmost the same as the number of correct responses.

Rats were administered a dose of a compound of Formula III, in which R¹is methyl and R² and R³ are each fluoro. The same task was applied andthe number of correct and incorrect responses was measured. The resultsare depicted in FIG. 4B. After administration of a compound of FormulaIII, the number of correct responses was far greater than beforetreatment and compared to the number of incorrect responses. These datarepresent an increase in the attention of the subject to the briefilluminations of lights relative to an untreated control.

Model For Reducing Effect of Nicotine. Food-deprived rats were trainedto press one lever for a food pellet after nicotine administration and asecond lever after vehicle administration. Pellets of food weredelivered intermittently, so that every twentieth response producedfood. Using this procedure, the only cue for the rat regarding whichlever occasionally pays off with a food pellet, is the subjective effectof the nicotine. When the rats were accurately and reliably identifyingthe nicotine injections (approximately all of its responses on the leverthat occasionally pays off after nicotine or saline), testing began. Therats were pretreated with a compound of Formula III before nicotineinjection, and the experiment progressed as described above, exceptresponses on either lever intermittently produced food. The data weremeasured and are depicted in Table 4. A 50% effective nicotine dose wasreduced to low levels of effectiveness upon administration of a compoundof Formula III.

TABLE 4 Compound Dose Effect nicotine only (control)   50% R¹ = Me 1.0mg/kg 7.65% R², R³ = F R¹ = allyl 3.0 mg/kg 22.4% R², R³ = F R¹ = butyl3.0 mg/kg 2.67% R², R³ = F

Model For Reducing Food Intake. Rats had access to food and were allowedto eat as much as they could during a one hour period daily. Rats wereadministered a compound of Formula III at varying doses. The followingcompounds were tested:

Code Compound of Formula III AHN R¹ = Me 1-055 R², R³ = F AHN R¹ = allyl2-005 R², R³ = F JHW R¹ = butyl 007 R², R³ = F 4-Cl R¹ = Me BZT R² = ClR³ = H GBR 12909 (com- par- ative)

Known compound1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine(“GBR 12909”) was also tested. Increasing doses of a compound of FormulaIII decreased food consumption (FIG. 5).

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

1.-44. (canceled)
 45. A compound of the formula (I):

in which: R¹ is selected from the group consisting of hydrogen, C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₆-C₂₀ aryl C₁-C₁₂ alkyl, C₅-C₂₀heteroaryl C₁-C₁₂ alkyl, C₁-C₁₂ aminoalkyl, C₁-C₁₂ alkoxy C₁-C₁₂ alkyl,C_(s)-C₂₀ heterocycloalkyl C₁-C₁₂ alkyl, C₁-C₁₂ alkylsulfonyl, C₂-C₁₂alkylcarbonyl, (N(C₆-C₂₀ aryl)amido)C₁-C₁₂ alkyl, (N(C₁-C₁₂alkyl)amido)C₁-C₁₂ alkyl, (N(C₆-C₂₀ aryl)amido)C₂-C₁₂ alkylcarbonyl,(N(C₁-C₁₂ alkyl)amido)C₂-C₁₂ alkylcarbonyl, C₁-C₁₂ alkylamido C₆-C₂₀aryl, and a polymer; R² and R³ are each independently selected from thegroup consisting of hydrogen, halo, C₁-C₁₂ alkyl, C₁-C₁₂ alkoxyl, nitro,cyanato, isocyanato, thiocyanato, amino, halo C₁-C₁₂ alkyl, hydroxyl,trihalo C₁-C₁₂ alkyl, and any combination thereof; m=1 to 5; n=1 to 3;R⁴ is selected from the group consisting of hydroxyl, carboxyl, C₁-C₁₂alkyl, C₁-C₁₂ alkoxyl, C₂-C₁₂ carboxyalkyl, C₂-C₁₂ alkyloxycarbonyl,C₆-C₂₀ aryloxycarbonyl, C₆-C₂₀ aryl C₂-C₁₂ alkyloxycarbonyl, C₂-C₁₂alkyloxycarbonyl C₁-C₁₂ alkyl, C₆- C₂₀ aryl, C₆-C₂₀ aryl C₂-C₁₂alkylcarbonyloxy C₁-C₁₂ alkyl, C₁-C₁₂ alkylsulfonyl, C₁-C₁₂hydroxyalkyl, formyl, C₂-C₁₂ formylalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkyloxycarbonyl C₂-C₁₂ alkenyl, and C₂-C₁₂ alkynyl; and Ar is a C₆-C₂₀monocyclic aryl group or a C₁₀-C₂₀ bicyclic aryl group; wherein any ofR¹, R², R³, and R⁴ other than hydrogen, halo, hydroxyl, nitro, cyanato,isocyanato, and thiocyanato may be further substituted with one or moresubstituents selected from the group consisting of halo, hydroxyl,cyanato, isocyanato, thiocyanato, amino, C₁-C₁₂ alkyl, amido, nitro,methoxyl, CF₃, azido, C₂-C₁₂ alkylcarbonylamino, C₁-C₁₂ alkylamino,C₂-C₁₂ alkylcarbonyl, and any combination thereof; or a pharmaceuticallyacceptable salt thereof, with the provisos that: (a) if Ar is phenyl,m=n=1, R¹ is CH₃, and R⁴ is β-COOCH₃, R² and R³ are not simultaneouslyhydrogen, R² and R³ are not simultaneously 4-halo or R² and R³ are notsimultaneously 4-methyl; (b) if Ar is phenyl, m=n=1, R¹ is H, and R⁴ isβ-COOCH₃, R² and R³ are not hydrogen or halo; (c) if Ar is phenyl, m=1,n=2, R¹ is H, R⁴ is β-COOCH₃, and R² is H, both R³ are not hydroxyl orboth R³ are not C₁-C₁₂ alkoxyl, (d) if Ar is phenyl, m=n=1, R¹ is CH₃,and R² and R³ are 4-fluoro, R⁴ is not COOC₂H₅, CO₂CH(CH₃)₂, CO₂CH₂Ph,CO₂CH₂CH₂Ph, CO₂CH₂CH₂Ph-4′-NO₂, CO₂CH₂CH₂Ph-4′-NH₂, CO₂CH₂CH₂Ph-3′-I,4′-NH₂, CO₂CH₂CH₂Ph-3′-I, 4′-N₃, or CO₂CH₂CH₂Ph-4′-NCS where R⁴ hasβ-configuration; (e) if Ar is phenyl, m=n=1, R¹ is CH₃, R⁴ is β-COOCH₃,and R² is hydrogen, R³ is not 4-halo or 4-methyl; (f) if Ar is phenyl,m=1, n=2, R¹ is CH₃, R⁴ is β-COOCH₃, and R² is hydrogen, R³ is nothydroxyl, alkoxyl, or methylcarbonyloxy; and (g) if R¹ is C₆-C₂₀ arylC₁-C₁₂ alkyl, optionally substituted with halo, R⁴ is β-COOCH₃, andm=n=1, R² and R³ are not simultaneously 4-halo.
 46. The compound or saltof claim 45, wherein the compound is of Formula II:


47. The compound or salt of claim 46, wherein R³ is fluoro or chloro.48. The compound or salt of claim 46, wherein m=n=1.
 49. The compound orsalt of claim 46, wherein Ar is selected from the group consisting ofphenyl, naphthyl, and biphenyl.
 50. The compound or salt of claim 46,wherein R¹ is selected from the group consisting of hydrogen, C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₆-C₂₀ aryl-C₁-C₁₂ alkyl, C₁-C₁₂ aminoalkyl,C₅-C₂₀ heterocycloalkyl-C₁-C₁₂ alkyl, and (N(C₆-C₂₀-aryl)amido)C₁-C₁₂alkyl.
 51. The compound or salt of claim 50, wherein R¹ is selected fromthe group consisting of methyl, ethyl, propyl, butyl, allyl,phenylbutyl, 2-aminoethyl, [2-(1H-indol-3-yl)-ethyl]-, and3-[(N-phenyl)amidopropyl].
 52. The compound or salt of claim 46, whereinR⁴ is selected from the group consisting of hydroxyl, carboxyl, C₁-C₁₂alkyl, C₁-C₁₂ alkoxyl, C₂-C₁₂ carboxyalkyl, C₂-C₁₂ alkyloxycarbonylC₁-C₁₂ alkyl, C₆-C₂₀ aryl, C₆-C₂₀ aryl C₂-C₁₂ alkylcarbonyloxy C₁-C₁₂alkyl, C₁-C₁₂ alkylsulfonyl, C₁-C₁₂ hydroxyalkyl, formyl, C₂-C₁₂formylalkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkyloxycarbonyl C₂-C₁₂ alkenyl, andC₂-C₁₂ alkynyl.
 53. The compound or salt of claim 52, wherein: Ar isphenyl; R¹ is selected from the group consisting of hydrogen, 2-propyl,(CH₂)_(p)CH₃, CH₂CF₃, CH₂(CH₂)_(p)OH, CH₂(CH₂)_(p)O(CH₂)_(q)CH₃,CH₂CH═CHX, 2-(1-piperidinyl)ethyl, 2-(4-morpholinyl)ethyl, or(CH₂)_(p)C₆H₄X, wherein X is selected from the group consisting of H,halo, hydroxyl, methoxyl, CF₃, nitro, amino, cyanato, NHCOCH₃, N(CH₃)₂,(CH₂)_(p)CH₃, C(O)CH₃, and C(CH₃)₃; p=0-6; q=0-4; and at least one of R²and R³ is selected from the group consisting of C₁-C₁₂ alkyl, C₂-C₁₂alkoxyl, nitro, cyanato, isocyanato, thiocyanato, amino, halo C₁-C₁₂alkyl, and trihalo C₁-C₁₂ alkyl.
 54. The compound or salt of claim 46,wherein: m=n=1; Ar is phenyl; R¹ is selected from the group consistingof hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₆-C₂₀ aryl-C₁-C₁₂ alkyl,C₁-C₁₂ aminoalkyl, C₅-C₂₀ heterocycloalkyl-C₁-C₁₂ alkyl, and(N(C₆-C₂₀-aryl)amido)C₁-C₁₂ alkyl; R² and R³ are halo; and R⁴ isselected from the group consisting of methyloxycarbonyl,ethyloxycarbonyl, hydroxymethyl, formyl, methyloxycarbonylethenyl,methyloxycarbonylethyl, ethenyl, 4-nitrophenylpropylcarbonyloxymethyl,and 4-aminophenylpropylcarbonyloxymethyl.
 55. The compound or salt ofclaim 54, wherein R¹ is selected from the group consisting of hydrogen,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₆-C₁₀ aryl-C₁-C₆ alkyl, C₁-C₆ aminoalkyl,C₅-C₁₀ heterocycloalkyl-C₁-C₆ alkyl, and (N(C₆-C₁₀-aryl)amido)C₁-C₆alkyl.
 56. The compound or salt of claim 55, wherein R¹ is selected fromthe group consisting of methyl, n-butyl, allyl, phenylbutyl,2-aminoethyl, [2-(1H-indol-3-yl)-ethyl]-, and 3-[(N-phenyl)amidopropyl].
 57. The compound or salt of claim 54, wherein R²and R³ are chloro.
 58. The compound or salt of claim 54, wherein R² andR³ are fluoro.
 59. The compound or salt of claim 54, wherein R⁴ ismethyloxycarbonyl or ethyloxycarbonyl.
 60. The compound or salt of claim54, wherein: m=n=1; Ar is phenyl; R¹ is selected from the groupconsisting of hydrogen, methyl, n-butyl, allyl, phenylbutyl,2-aminoethyl, [2-(1H-indol-3-yl)-ethyl]-, and 3-[(N-phenyl)amidopropyl];R² and R³ are 4-fluoro or 4-chloro; and R⁴ is selected from the groupconsisting of hydroxymethyl, formyl, methyloxycarbonylethenyl,methyloxycarbonylethyl, ethenyl, 4-nitrophenylpropylcarbonyloxymethyl,and 4-aminophenylpropylcarbonyloxymethyl.
 61. The compound or salt ofclaim 60, wherein R¹ is methyl.
 62. The compound or salt of claim 45,wherein the compound is selected from the group consisting ofS-(+)-2β-carboethoxy-3α-[bis(4-chlorophenyl)methoxy]tropane,S-(−)-2β-carboethoxy-3α-[bis(4-chlorophenyl)methoxy]tropane, andS-(±)-2β-carboethoxy-3α-[bis(4-chlorophenyl)methoxy]tropane.
 63. Apharmaceutical composition comprising a compound or salt of claim 45 anda pharmaceutically acceptable carrier.
 64. A method of treating apatient for a mental disorder comprising administering to the patient aneffective amount of a compound or salt of claim
 45. 65. The method ofclaim 64, wherein the mental disorder is selected from the groupconsisting of conduct disorders, alcohol addiction, tobacco addiction,nicotine addiction, drug addiction, sleep disorders, inhalationdisorders, obesity, Parkinsonism, female and male orgasmic disorders,female and male sexual arousal disorders, hypoactive sexual desiredisorder, and anxiety, stress and/or depression disorders.
 66. Themethod of claim 65, wherein the Parkinsonism is Parkinson's disease. 67.A method of selectively imaging cocaine binding sites of the centralnervous system of a patient, the method comprising administering to thecentral nervous system of the patient a compound or salt of claim 45 anddetecting the binding of that compound or salt to the central nervoussystem tissue.
 68. A method of detecting or monitoring Parkinsonism in apatient, the method comprising administering to the patient a detectablylabeled compound or salt of claim 45 and detecting the binding of thatcompound or salt to the central nervous system tissue.
 69. A method ofincreasing attention relative to an untreated control in a mammalcomprising administering to the mammal an effective amount of a compoundof the formula (III):

wherein R¹ is C₁-C₁₂ alkyl or C₂-C₁₂ alkenyl; and R² and R³ are eachindependently hydrogen or halo.
 70. A method of reducing the effect ofnicotine by at least 50% in a mammal comprising administering to themammal an effective amount of a compound of the formula (III):

wherein R¹ is C₁-C₁₂ alkyl or C₂-C₁₂ alkenyl; and R² and R³ are eachindependently hydrogen or halo.
 71. A method of reducing food intake ina mammal comprising administering to the mammal an effective amount of acompound of the formula (III):

wherein R¹ is C₁-C₁₂ alkyl or C₂-C₁₂ alkenyl; and R² and R³ are eachindependently hydrogen or halo.